Indolinone combinatorial libraries and related products and methods for the treatment of disease

ABSTRACT

The present invention relates to organic molecules capable of modulating, regulating and/or inhibiting protein kinase signal transduction. Such compounds are useful for the treatment of diseases related to unregulated protein kinase signal transduction, including cell proliferative diseases such as cancer, atherosclerosis, arthritis and restenosis and metabolic diseases such as diabetes. The present invention features indolinone compounds that potently inhibit protein kinases and related products and methods. Inhibitors specific to the FLK protein kinase can be obtained by adding chemical substituents to the 3-[(indole-3-yl)methylene]-2-indolinone, in particular at the 1′ position of the indole ring. Indolinone compounds that specifically inhibit the FLK and platelet derived growth factor protein kinases can harbor a tetrahydroindole or cyclopentano-b-pyrrol moiety. Indolinone compounds that are modified with substituents, particularly at the 5 position of the oxindole ring, can effectively activate protein kinases. This invention also features novel hydrosoluble indolinone compounds that are tyrosine kinase inhibitors and related products and methods.

RELATED APPLICATIONS

[0001] This application relates to U.S. patent applications Ser. No.60/031,586, filed Dec. 5, 1996, entitled “FLK Specific IndolinoneCompounds and Related Products and Methods for the Treatment of Disease”by McMahon et al. (Lyon & Lyon Docket No. 223/146); Ser. No. 60/045,566,filed May 5, 1997, entitled “FLK Specific Indolinone Compounds andRelated Products and Methods for the Treatment of Disease” by McMahon etal. (Lyon & Lyon Docket No. 225/148); Ser. No. 60/032,546, filed Dec. 5,1996, entitled “HYDROSOLUBLE INDOLINE TYROSINE KINASE INHIBITORS” byMcMahon et al. (Lyon & Lyon Docket No. 223/062); Ser. No. 60/045,715,filed Dec. 5, 1996, entitled “SUBSTITUTED3-[(TETRAHYDROINDOLE-2-YL)METHYLENE]-2-INDOLINONE AND3-[(CYCLOPENTANO-b-PYRROL-2-YL)METHYLENE]-2-INDOLINONE COMPOUNDS” byMcMahon et al. (Lyon & Lyon Docket No. 225/145); Ser. No. 60/031,588,filed Dec. 5, 1996, entitled “5-SUBSTITUTED INDOLINONE COMPOUNDS ASMODULATORS OF PROTEIN KINASE ACTIVITY” by McMahon et al. (Lyon & LyonDocket No. 223/061); Ser. No. 60/045,714, filed May 5, 1997, entitled“5-SUBSTITUTED INDOLINONE COMPOUNDS AS MODULATORS OF PROTEIN KINASEACTIVITY” by McMahon et al. (Lyon & Lyon Docket No. 225/146); Ser. No.60/032,547, filed Dec. 5, 1996, entitled “SUBSTITUTED3-[(TETRAHYDROINDOLE-2-YL)METHYLENE]-2-INDOLINONE AND3-[(CYCLOPENTANO-b-PYRROL-2-YL)METHYLENE]-2-INDOLINONE COMPOUNDS” byMcMahon et al. (Lyon & Lyon Docket No. 223/060); Ser. No. 60/046,843,filed May 5, 1997, entitled “HYDROSOLUBLE INDOLINE TYROSINE KINASEINHIBITORS” by McMahon et al. (Lyon & Lyon Docket No. 225/147); Ser. No.60/031,585, filed Dec. 5, 1996, entitled “SUBSTITUTED3-[(INDOLE-3-YL)METHYLENE]-2-INDOLINONE COMPOUNDS” by McMahon et al.(Lyon & Lyon Docket No. 223/059); Ser. No. 60/031,565, filed May 5,1997, entitled “SUBSTITUTED 3-[(INDOLE-3-YL)METHYLENE]-2-INDOLINONECOMPOUNDS” by McMahon et al. (Lyon & Lyon Docket No. 225/144) and thisapplication also relates to U.S. patent application Ser. No. 08/702,232,filed Aug. 23, 1996, entitled “Indolinone Combinatorial Libraries andRelated Products and Methods for the Treatment of Disease” by Tang etal. (Lyon & Lyon Docket No. 221/187) which is a continuation-in-partapplication of U.S. patent application Ser. Nos. 08/655,225, filed Jun.5, 1996, entitled “3-(2′Halobenzylidenyl)-2-Indoline Compounds for theTreatment of Disease” by Tang et al. (Lyon & Lyon Docket No. 223/299);Ser. No. 08/655,226, filed Jun. 5, 1996, entitled“3-(4′-Dimethylaminobenzylidenyl)-2-Indolinone and Analogues Thereof forthe Treatment of Disease” by Tang et al. (Lyon & Lyon Docket No.223/300); Ser. No. 08/655,223, filed Jun. 5, 1996, entitled“3—Heteroaryl-2-Indolinone Compounds for the Treatment of Disease” byTang et al. (Lyon & Lyon Docket No. 223/301); Ser. No. 08/655,224, filedJun. 5, 1996, entitled “3-(2′-Alkoxybenzylidenyl)-2-Indolinone andAnalogues Thereof for the Treatment of Diseases” by Tang et al. (Lyon &Lyon Docket No. 223/3020, and, Ser. No. 08/659,191, filed Jun. 5, 1996,entitled “3-(4′Bromobenzylindenyl)-2-Indolinone and Analogues Thereoffor the Treatment of Disease” by Tang et al. (Lyon & Lyon Docket No.223/303), all of which are continuations-in-part of U.S. patentapplication Ser. No. 08/485,323, filed Jun. 7, 1995, entitled“Benzylidene-Z-Indoline Compounds for the Treatment of Disease” by Tanget al. (Lyon & Lyon Docket No. 223/298) all of which are incorporatedherein by reference in their entirety, including any drawings.

INTRODUCTION

[0002] The present invention relates to novel compounds capable ofmodulating, regulating and/or inhibiting protein kinase signaltransduction. The present invention is also directed to methods ofregulating, modulating or inhibiting protein kinases, whether of thereceptor or non-receptor class, for the prevention and/or treatment ofdisorders related to unregulated protein kinase signal transduction,including cell proliferative and metabolic disorders.

BACKGROUND OF THE INVENTION

[0003] The following description of the background of the invention isprovided to aid in understanding the invention, but is not admitted tobe or describe prior art to the invention.

[0004] Protein kinases and protein phosphatases regulate a wide varietyof cellular processes including metabolism, cell proliferation, celldifferentiation, and cell survival by participating in signaltransduction pathways. Alterations in the cellular function of a proteinkinase or protein phosphatase can give rise to various diseased statesin an organism. For example, many types of cancer tumors are associatedwith increases in the activity of specific protein kinases. Cell andtissue degeneration can also be associated with decreases in theactivity of particular protein kinases.

[0005] Cellular signal transduction is a fundamental mechanism wherebyextracellular stimuli are relayed to the interior of cells. One of thekey biochemical mechanisms of signal transduction involves thereversible phosphorylation of proteins. Phosphorylation of amino acidsregulates the activity of mature proteins by altering their structureand function.

[0006] Phosphate most often resides on the hydroxyl moiety of serine,threonine, or tyrosine amino acids in proteins. Enzymes that mediatephosphorylation of cellular effectors fall into two classes. Whileprotein phosphatases hydrolyze phosphate moieties from phosphorylprotein substrates, protein kinases transfer a phosphate moiety fromadenosine triphosphate to protein substrates. The converse functions ofprotein kinases and protein phosphatases balance and regulate the flowof signals in signal transduction processes.

[0007] Protein kinases are divided into two groups—receptor andnon-receptor type proteins. Receptor protein kinases comprise anextracellular region, a transmembrane region, and an intracellularregion. Part of the intracellular region of receptor protein kinasesharbors a catalytic domain. While non-receptor protein kinases do notharbor extracellular or transmembrane regions, they do comprise a regionsimilar to the intracellular regions of their receptor counterparts.

[0008] Protein kinases are divided further into three classes based uponthe amino acids they act upon. Some incorporate phosphate on serine orthreonine only, some incorporate phosphate on tyrosine only, and someincorporate phosphate on serine, threonine, and tyrosine.

[0009] In an effort to discover novel treatments for diseases,biomedical researchers and chemists have designed, synthesized, andtested molecules that inhibit the function of protein kinases. Somesmall organic molecules form a class of compounds that modulate thefunction of protein kinases.

[0010] The compounds that can traverse cell membranes and are resistantto acid hydrolysis are potentially advantageous therapeutics as they canbecome highly bioavailable after being administered orally to patients.However, many of these protein kinase inhibitors only weakly inhibit thefunction of protein kinases. In addition, many inhibit a variety ofprotein kinases and will therefore cause multiple side-effects astherapeutics for diseases.

[0011] Some indolinone compounds, however, form classes of acidresistant and membrane permeable organic molecules that potently inhibitonly specific protein kinases. Indolinone synthesis, methods of testingthe biological activity of indolinones, and inhibition patterns of someindolinone derivatives are described in International Patent PublicationNo. WO96/40116, published Dec. 19, 1996 entitled“Benzylidene-Z-Indolinone Compounds for the Treatment of Disease” byTang et al. (Lyon & Lyon Docket No. 223/298) and International PatentPublication No. WO96/22976, published Aug. 1, 1996 by Ballinari et al.,both of which are incorporated herein by reference in their entirety,including any drawings.

[0012] Despite the significant progress that has been made in developingindolinone based pharmaceuticals, there remains a need in the art toidentify the particular structures and substitution patterns that causeinhibition of particular protein kinases and other specified biologicalactivities.

SUMMARY OF THE INVENTION

[0013] The present invention relates to organic molecules capable ofmodulating, regulating and/or inhibiting protein kinase signaltransduction. Such compounds are useful for the treatment of diseasesrelated to unregulated protein kinase signal transduction, includingcell proliferative diseases such as cancer, atherosclerosis, arthritisand restenosis and metabolic diseases such as diabetes. The proteinkinases effected include, but are not limited to Flk, FGFR, PDGFR, andraf.

[0014] The present invention features indolinone compounds that potentlyinhibit protein kinases and related products and methods. Inhibitorsspecific to the FLK protein kinase can be obtained by adding chemicalsubstituents to the 3-[(indole-3-yl)methylene]-2-indolinone, inparticular at the 1′ position of the indole ring. Indolinone compoundsthat specifically inhibit the FLK and platelet derived growth factorprotein kinases can harbor a tetrahydroindole or cyclopentano-b-pyrrolmoiety. Indolinone compounds that are modified with substituents,particularly at the 5 position of the oxindole ring, can effectivelyactivate protein kinases. This invention also features novelhydrosoluble indolinone compounds that are tyrosine kinase inhibitorsand related products and methods.

[0015] The compounds of the invention represent a new generation ofpotential therapeutics for diseases caused by one or more non-functionalprotein kinases. Neurodegenerative diseases fall into this class ofdiseases, including, but not limited to Parkinson's Disease andAlzheimers disease. The compounds can be modified such that they arespecific to their target or targets and will subsequently cause few sideeffects and thus represent a new generation of potential cancertherapeutics. These properties are significant improvements over thecurrently utilized cancer therapeutics that cause multiple side effectsand deleteriously weaken patients.

[0016] It is believed the compounds of the invention will minimize andobliterate solid tumors by specifically inhibiting the activity of theFLK protein kinase, or will at least modulate or inhibit tumor growthand/or metastases. The FLK protein kinase regulates proliferation ofblood vessels during angiogenesis. Increased rates of angiogenesisaccompany cancer tumor growth in cells as cancer tumors must benourished by oxygenated blood during growth. Therefore, inhibition ofthe FLK protein kinase and the corresponding decreases in angiogenesiswill starve tumors of nutrients and most likely obliterate them.

[0017] While a precise understanding of the mechanism by which compoundsinhibit PTKs (e.g., the fibroblast growth factor receptor 1 [FGFR1]) isnot required in order to practice the present invention, the compoundsare believed to interact with the amino acids of the PTKs' catalyticregion. PTKs typically possess a bi-lobate structure, and ATP appears tobind in the cleft between the two lobes in a region where the aminoacids are conserved among PTKs; inhibitors of PTKs are believed to bindto the PTKs through non-covalent interactions such as hydrogen bonding,Van der Waals interactions, and ionic bonding, in the same generalregion that ATP binds to the PTKs. More specifically, it is thought thatthe oxindole component of the compounds of the present invention bindsin the same general space occupied by the adenine ring of ATP.Specificity of an indolinone PTK inhibitor for a particular PTK may beconferred by interactions between the constituents around the oxindolecore with amino acid domains specific to individual PTKs. Thus,different indolinone substitutents may contribute to preferentialbinding to particular PTKs. The ability to select those compounds activeat different ATP (or other nucleotide) binding sites makes them usefulin targeting any protein with such a site, not only protein tyrosinekinases, but also serine/threonine kinases and protein phosphatases.Thus, such compounds have utility for in vitro assays on such proteinsand for in vivo therapeutic effect through such proteins. In one aspectthe invention features a combinatorial library of indolinone compounds.The library includes a series of at least ten (preferably at least50-100, more preferably at least 100-500, and most preferably at least500-5,000) indolinones that can be formed by reacting an oxindolecompound with an aldehyde. In preferred embodiments the indolinones inthe library can be formed by reacting a type A oxindole with a type Baldehyde. Type A oxindoles and type B aldehydes are shown in FIGS. 1 and2 respectively (and Tables 11 and 12 respectively), as explained indetail below. As can be seen, in the figures the oxindoles are labeled01, 02, 03, . . . and the aldehydes are named A1, A2, A3, . . . Thus,one can readily appreciate that the combinatorial library could includeany and all combinations of oxindoles and aldehydes, including theindolinones resulting from 01 and A1, 01 and A2, 01 and A3, 02 and A1,02 and A2, 02 and A3, 03 and A1, 03 and A2, 03 and A3 and so on.Similarly, the indolinones in the library can be formed by anycombination of the oxindoles in Table 11 with any of the aldehydeslisted in FIG. 2 or Table 12. Finally, the indolinones may also, ofcourse, come from any combination of aldehydes listed in Table 12 withany oxindoles from FIG. 1 or Table 11.

[0018] The term “combinatorial library” refers to a series of compounds.In the present case, the combinatorial library contains a series ofindolinone compounds that can be formed by reacting an oxindole and analdehyde. A wide variety of oxindoles and aldehydes may be used tocreate the library of indolinones.

[0019] The term .“indolinone” is used as that term is commonlyunderstood in the art and includes a large subclass of substituted orunsubstituted compounds that are capable of being synthesized from analdehyde moiety and an oxindol moiety, such as the compounds shownbelow.

[0020] The term “type A oxindole” is meant to include any and all of theoxindoles set forth in FIG. 1 and Table 11. Oxindoles, as that term isused herein, typically have the structure set forth below:

[0021] wherein,

[0022] (a) A₃, A₂, A₃, and A₄ are independently carbon or nitrogen;

[0023] (b) R₁ is hydrogen or alkyl;

[0024] (c) R₂ is oxygen or sulfur;

[0025] (d) R₃ is hydrogen;

[0026] (e) R₄, R₅, R₆ and R₇ (i) are each independently selected fromthe group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl,alkaryloxy, halogen, trihalomethyl, S(O) R, SO₂NRR′, SO₃R, SR, NO₂,NRR′, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_(n)CO₂R, and CONRR′ or (ii)any two adjacent R₄, R₅, R₆, and R₇ taken together form a fused ringwith the aryl portion of the oxindole-based portion of the indolinone.

[0027] It is to be understood that when A₁, A₂, A₃, and A₄ is nitrogenor sulfur that the corresponding R₄, R₅, R₆, or R₇ is nothing and thatthe corresponding bond shown in structure I does not exist.

[0028] Examples of oxindoles having such fused rings (as described in(e) (ii) above) are shown in FIG. 1, compounds 044, 045, 047, 048, 050,051, 052, 053, 055, 056, 058, 059, 061, 062, 064, 066, 067, 069, 070,and 073. Other examples of suitable fused rings include the following:

[0029] The six membered rings shown above also exemplify possible Arings in the structures II, III and IV.

[0030] The term “type B aldehyde” includes any and all of the aldehydesset forth in FIG. 2 and Table 11. The term “aldehyde” is used as iscommonly understood in the art to include substituted and unsubstitutedaldehydes of the structure R_(d)CHO where R_(d) can be a wide variety ofsubstituted or unsubstituted groups such as alkyl and aryl.

[0031] In yet another aspect, the invention provides a method ofsynthesizing an indolinone by reacting a type A oxindole with a type Baldehyde. The method of making the indolinones of the present inventionmay involve creating a combinatorial library of compounds as describedabove, testing each compound in biological assays such as thosedescribed herein, selecting one or more suitable compounds andsynthesizing the selected compound or compounds.

[0032] Also featured is an indolinone compound having formula II or III:

[0033] wherein:

[0034] (a) A₁, A₂, A₃, and A₄ are independently carbon or nitrogen;

[0035] (b) R₁ is hydrogen or alkyl;

[0036] (c) R₂ is oxygen or sulfur;

[0037] (d) R₃ is hydrogen;

[0038] (e) R₄, R₅, R₆, and R₇ (i) are each independently selected fromthe group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl,alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′, SO₃R, SR, NO₂, NRR′,OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_(n)CO₂R, and CONRR′ or (ii) anytwo adjacent R₄, R₅, R₆, and R₇ taken together form a fused ring withthe aryl ring of the oxindole-based portion of the indolinone;

[0039] (f) R_(2′), R_(3′), R_(4′), R_(5′), and R_(6′) are eachindependently selected from the group consisting of hydrogen, alkyl,alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl,S(O)R, SO₂NRR′, SO₃R, SR, NO₂, NRR′, OH, CN, C(O)R, OC(O)R, NHC(O)R,(CH₂)_(n)CO₂R, and CONRR′;

[0040] (g) n is 0, 1, 2, or 3;

[0041] (h) R is hydrogen, alkyl or aryl;

[0042] (i) R′ is hydrogen, alkyl or aryl; and

[0043] (j) A is a five membered heteroaryl ring selected from the groupconsisting of thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole,1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole,2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole,1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole,1,2,3,5-thiatriazole, and tetrazole, optionally substituted at one ormore positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy,halogen, trihalomethyl, S(O)R, SO₂NRR′, SO₃R, SR, NO₂, NRR′, OH, CN,C(O)R, OC(O)R, NHC(O) R, (CH₂)_(n)CO₂R or CONRR′.

[0044] As used herein, the term “compound” is intended to includepharmaceutically acceptable salts, esters, amides, prodrugs, isomers andmetabolites of the base compound.

[0045] In preferred embodiments of structure III, the A substituent maybe a five membered heterocycle of formula IV shown below:

[0046] wherein D, E, F, and G are nitrogen, carbon, or sulfur atoms. Thespecific juxtaposition of groups D-G is limited to examples ofheterocyclic groups known in the chemistry arts, such as the fused ringsreferred to above and all of which may be optionally substituted asdescribed above in paragraph (j).

[0047] In preferred embodiments, the aryl ring (“the A ring”) of theoxindole-derived portion of the indolinone (i.e., the ring shown instructures II and III with A₁, A₂, A₃, and A₄) has a polar substituent,preferably selected from the group consisting of NH₂, COOH, SO₃H, Br,Cl, I, F, COCH₂CH₂COOH, COCH₂Cl, piperazine, and CH₂CH₂NH₂ at the 4, 5,6, and 7 carbon atom positions (identified by substituents R₄, R₅, R₆,and R₇ respectively in structures V and VI), most preferablyhydrophillic groups such as NH₂, COOH, SO₃, COCH₂CH₂COOH, piperazine andCH₂CH₂NH₂.

[0048] One approach to choosing target inhibitors of the FGFR (a proteinkinase receptor linked to various disorders, such as Pfeiffer,Jackson-Weiss and Cruzon syndromes; dysplasias and hypochondroplasia;dwarfism; bone dysplasia; and developmental disorders involves selectingtarget compounds with a substituent on the A ring that mimics thetriphosphate of ATP and thereby increases the affinity of targetcompounds for the active-site of the FGFR. Hydrophillic groups may actto mimic the triphosphate at ATP, and also to improve the solubility ofthe final inhibitor. Without being bound to any theory, it appears thatthe trans form of the indolinones is generally a more favorable form forFGFR inhibitors.

[0049] Amine-based substituents at positions 4, 5, and 6 at the A ringof structures II and III are a preferred class of substituents and anespecially preferred class are amines of the structure:

[0050] wherein R_(a) is CO(CH₂)₂COOH, aryl, alkyl, or contains COOH, OH,or NH₂. These types of groups provide steric hindrance in order to forcethe isomer into a trans conformation which may be a favored property ofFGFR inhibition and acts as a linker to a hydrophillic group.

[0051] Another favored class of substituents on the aryl ring ofstructures II and III includes piperazine type substituents of thestructure:

[0052] wherein R_(b) is preferably a negatively charged group, such as anegatively charged alkyl or acyl.

[0053] Yet another preferred class of substituents for the aryl ring ofstructures II and III are C—COR groups of the formula:

[0054] wherein R_(c) is a hydrophilic or negatively charged group,preferably at the 5 and/or 6 positions of the A ring of structures IIand III, such as amide, ester, CH₂CH₂COOH, CH₂Cl, or piperazine. R_(c)could also be linked to the aryl ring by a sp3 carbon or could beattached as R_(c)O₃S—.

[0055] Yet another preferred set of substituents on the aryl ring arefused heterocyclic rings which can be synthesized by acylation of thearylamine followed by alkylation of the heterocyclic ring systems.Examples of several such compounds are set forth in FIG. 1, compounds044, 045, 047, 048, 050, 051, 052, 053, 055, 056, 058, 059, 061, 062,064, 066, 067, 069, 070, and 073.

[0056] In another aspect, the invention features a3-[(indole-3-yl)methylene]-2-indolinone compound having a substituent atthe 1′ position of the indole ring. The substituent at the 1′ positionof the indole ring is selected from the group consisting of

[0057] (a) alkyl that is optionally substituted with a monocyclic orbicyclic five, six, eight, nine, or ten membered heterocyclic ring,where the ring is optionally substituted with one or more halogen, ortrihalomethyl substituents;

[0058] (b) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents;

[0059] (c) an aldehyde or ketone of formula —CO—R12, where R12 isselected from the group consisting of hydrogen, alkyl, and a five or sixmembered heterocyclic ring;

[0060] (d) a carboxylic acid of formula —(R₁₃)_(n)—COOH or ester offormula —(R₁₄)_(m)—COO—R₁₅, where R₁₃, R₁₄, and R₁₅ are independentlyselected from the group consisting of alkyl and a five or six memberedheterocyclic ring and m and n are independently 0 or 1;

[0061] (e) a sulfone of formula —(SO₂)—R₁₆, where R₁₆ is selected fromthe group consisting of alkyl and a five or six membered heterocyclicring, where the ring is optionally substituted with an alkyl moiety;

[0062] (f) -(R₁₇)_(n)-(indole-1-yl) or-(R₁₈)m-CHOH—(R₁₉)p-(indole-1-yl), where the indol moiety is optionallysubstituted where R₁₇, R₁₈, and R₁₉ are alkyl, and where m, n, and p areindependently 0 or 1; and

[0063] (g) taken together with a 2′ substituent of the indole ring formsa five or six membered heterocyclic ring.

[0064] The term “alkyl” refers to a straight-chain, branched, or cyclicsaturated aliphatic hydrocarbon. The alkyl group is preferably 1 to 10carbons, more preferably a lower alkyl of from 1 to 7 carbons, and mostpreferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl andthe like. The alkyl group may be substituted and some typical alkylsubstituents include hydroxyl, cyano, alkoxy, oxygen, sulfur, nitroxy,halogen, —N(CH₃)₂, amino, and —SH.

[0065] The term “methyl” refers to a saturated alkyl moiety of onecarbon. The term “ethyl” refers to a saturated alkyl moiety of twocarbons. The term “propyl” refers to a saturated alkyl moiety of threecarbons. The term “butyl” refers to a saturated alkyl moiety of fourcarbons. The term “pentyl” refers to a saturated alkyl moiety of fivecarbons.

[0066] The term “aryl” refers to an aromatic group which has at leastone ring having a conjugated pi electron system and includes bothcarbocyclic aryl (e.g. phenyl) and heterocyclic aryl groups (e.g.pyridine). Aryl moieties include monocyclic, bicyclic, and tricyclicrings, where each ring has preferably five or six members. The arylmoiety may be substituted and typical aryl substituents include halogen,trihalomethyl, hydroxyl, —SH, —OH, —NO₂, amine, thioether, cyano,alkoxy, alkyl, and amino.

[0067] The terms “heterocycle” or “heterocyclic” refer to compounds thatform a ring and contain up to four hetero atoms, the remainder of theatoms forming the ring being carbon. Thus, for example, each ring in thestructure can contain zero, one, two, three, or four nitrogen, oxygen,or sulfur atoms within the ring. The ring can preferably be saturatedwith hydrogen atoms, more preferably harbor one or more unsaturations,and most preferably contain an aryl conjugated pi electron system. Therings are preferably eleven, twelve, thirteen, or fourteen memberedrings, more preferably eight, nine, or ten membered rings, and mostpreferably five or six membered rings. Examples of such rings are furyl,thienyl, pyrrol, imidazolyl, indolyl, pyridinyl, thiadiazolyl,thiazolyl, piperazinyl, dibenzfuranyl, dibenzthienyl. The heterocyclicrings of the invention may be optionally substituted with one or morefunctional groups which are attached commonly to such rings, such as,e.g., hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano,cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, oxo,alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and thelike. Structures of some preferred heterocyclic rings are the fusedrings that have been shown above.

[0068] The term “aldehyde” refers to a chemical moiety with formula—(R)_(n)—CHO, where R is selected from the group consisting of alkyl oraryl and n is 0 or 1.

[0069] The term “ketone” refers to a chemical moiety with formula—(R)_(n)—CO—R′, where R and R′ are selected from the group consisting ofalkyl or aryl and n is 0 or 1.

[0070] The term “carboxylic acid” refers to a chemical moiety withformula —(R)_(n)—COOH, where R is selected from the group consisting ofalkyl or aryl and n is 0 or 1.

[0071] The term “ester” refers to a chemical moiety with formula—(R)_(n)—COOR′, where R and R′ are independently selected from the groupconsisting of alkyl or aryl and n is 0 or 1.

[0072] The term “sulfone” refers to a chemical moiety with formula—SO₂—R, where R is selected from the group consisting of alkyl or aryl.

[0073] The term “pharmaceutically acceptable salt” refers to aformulation of a compound that does not cause significant irritation toan organism and does not abrogate the biological activity and propertiesof the compound. Pharmaceutical salts can be obtained by reacting acompound of the invention with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

[0074] The term “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs may be easier to administer than theparent drug in some situations. For example, the prodrug may bebioavailable by oral administration but the parent is not, or theprodrug may improve solubility to allow for intravenous administration.

[0075] A preferred embodiment of the invention relates to compound ofthe following formula,

[0076] where (a) R₁ as is described above for the substituent at the 1′position of the indole ring;

[0077] (b) R₂, R₃, R₄, R₅, and R₆ are independently selected from thegroup consisting of,

[0078] (i) hydrogen;

[0079] (ii) alkyl that is optionally substituted with a monocyclic orbicyclic five, six, eight, nine, or ten membered heterocyclic ring,where the ring is optionally substituted with one or more halogen, ortrihalomethyl substituents;

[0080] (iii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents;

[0081] (iv) a ketone of formula —CO—R₂₀, where R₂₀ is selected from thegroup consisting of hydrogen, alkyl, or a five or six memberedheterocyclic ring

[0082] (v) a carboxylic acid of formula —(R21)n-COOH or ester of formula—(R₂₂)—COO—R₂₃, where R₂₁, R₂₂, and R₂₃ and are independently selectedfrom the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1;

[0083] (vi) halogen;

[0084] (vii) an alcohol of formula (R24)m-OH or an ether of formula—(R₂₄)_(n)—O—R₂₅, where R₂₄ and R₂₅ are independently selected from thegroup consisting of alkyl and a five or six membered heterocyclic ringand m and n are independently 0 or 1;

[0085] (viii) —NR₂₆R₂₇, where R₂₆ and R₂₇ are independently selectedfrom the group consisting of hydrogen, oxygen, alkyl, and a five or sixmembered heterocyclic ring;

[0086] (ix) —NHCOR₂₈, where R₂₈ is selected from the group consisting ofhydroxyl, alkyl, and a five or six membered heterocyclic ring, where thering is optionally substituted with alkyl, halogen, carboxylate, orester;

[0087] (x) —SO₂NR₂₉R₃₀, where R₂₉ and R₃₀ are selected from the groupconsisting of hydrogen, oxygen, alkyl, and a five or six memberedheterocyclic ring;

[0088] (xi) any two of R₃, R₄, R₅, or R₆ taken together form a bicyclicor tricyclic moiety fused to the six membered ring of the indole, whereeach ring in the multicyclic moiety is a five or six memberedheterocyclic ring;

[0089] (c) R₇, R₈, R₉, and R₁₀ are independently selected from the groupconsisting of,

[0090] (i) hydrogen;

[0091] (ii) alkyl that is optionally substituted with a monocyclic orbicyclic five, six, eight, nine, or ten membered heterocyclic ring,where the ring is optionally substituted with one or more halogen,aldehyde, or trihalomethyl substituents;

[0092] (iii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents;

[0093] (iv) an aldehyde or ketone of formula —CO—R₃₁, where R₃₁ isselected from the group consisting of hydrogen, alkyl, or a five or sixmembered heterocyclic ring;

[0094] (v) a carboxylic acid of formula —(R32)n-COOH or ester of formula—(R₃₃)_(m)—COO—R₃₄, where R₃₂, R₃₃, and R₃₄ and are independentlyselected from the group consisting of alkyl or a five or six memberedheterocyclic ring and n and m are independently 0 or 1;

[0095] (vi) halogen;

[0096] (vii) an alcohol of formula (R₃₅)_(m)—OH or an ether of formula—(R₃₅)n-O—R₃₆, where R₃₅ and R₃₆ are independently chosen from the groupconsisting of alkyl or a five or six membered heterocyclic ring and mand n are independently 0 or 1;

[0097] (viii) —NR₃₇R₃₈, where R ₃₇ and R₃₈ are independently selectedfrom the group consisting of hydrogen, oxygen, alkyl, and a five or sixmembered heterocyclic ring;

[0098] (ix) —NHCOR₃₉, where R₃₉ is selected from the group consisting ofhydroxyl, alkyl, and a five or six membered heterocyclic ring, where thering is optionally substituted with alkyl, halogen, carboxylate, orester;

[0099] (x) —SO2NR₄₀R₄₁, where R₄₀ and R₄₁ are selected from the groupconsisting of hydrogen, oxygen, alkyl, and a five or six memberedheterocyclic ring;

[0100] (xi) any two of R₇, R₈, R₉, or R₁₀ taken together form a bicyclicor tricyclic heterocyclic moiety fused to the six membered ring of theindole, where each ring in the multicyclic moiety is a five or sixmembered heterocyclic ring; and

[0101] (d) R₁₁ is hydrogen or alkyl; provided that at least one of R₁,R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, or R₁₀ is alkyl or provided that atleast four of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, or R₁₀ are nothydrogen.

[0102] In preferred embodiments of the invention as shown in structure Vabove, R₁ is preferably a lower alkyl, branched or unbranched, morepreferably an unbranched lower alkyl (e.g., ethyl, propyl, isopropyl,butyl, tertiary butyl, pentyl), and most preferably a methyl moiety.

[0103] In other preferred embodiments one or more of R₁, R₂, R₃, R₄, R₅,R₆, R₇, R₈, R₉, and R₁₀ of structure V are a heterocyclic ring. Theheterocycle is preferably selected from the group consisting of five,six, eight, nine, ten, eleven, twelve, thirteen, and fourteen memberedaryl or non-aryl rings. The heterocycles can be furyl, thienyl, pyrrol,imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl,dibenzfuranyl, dibenzthienyl, 2-aminothiazol-4-yl,2-amino-5-chlorothiazol-4-yl, 2-amino-thiadiazol-4-yl,2,3-dioxopiperazinyl, 4-alkylpiperazinyl, 2-iodo-3-dibenzfuranyl, and3-hydroxy-4-dibenzthienyl. R₂ preferably is lower alkyl, more preferablymethyl, or phenyl or biphenyl preferably mono-substituted with halogen.R₃, R₄, R₅ and mono-R₆ preferably are selected from the group consistingof hydrogen, unsubstituated lower alkyls, halogen, methoxy, carboncyclicand ether. R11 is preferably hydrogen.

[0104] In especially preferred embodiments of structure V, R₁ is methyland R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, and R₁₁ are hydrogen, or R₁ andR₇ are methyl and R₂, R₃, R₄, R₆, R₉, R₁₀, and R₁₁ are hydrogen. Otherespecially preferred compounds are set forth in the tables and examplesset forth herein.

[0105] In another aspect, the invention features a method ofsynthesizing an indolinone compound, where the method comprises thesteps of:

[0106] (a) reacting an aldehyde of formula VI with an oxindol of formulaVII,

[0107] where R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, and R₁₁ aredescribed herein; and

[0108] (b) separating the indolinone compound from the aldehyde andoxindol reactants.

[0109] The term “synthesizing” defines a method of combining multiplecompounds together and/or chemically modifying the compound(s) in acontrolled environment. A controlled environment preferably includes aglass vessel, a stirring rod or bar, a heating or cooling source, andspecific organic solvents.

[0110] The term “reacting” refers to mixing two compounds together in acontrolled environment. The compounds that are mixed together andreacted with one another are termed “reactants”.

[0111] The term “separating” describes methods of segregating compoundsfrom one or more other compounds. Compounds can be separated from oneanother by using techniques known in the art which include, but are notlimited to, column chromatography techniques and solvent phaseseparation techniques.

[0112] In another aspect, the invention features optionally substituted3-[(tetrahydroindole-2-yl)methylene]-2-indolinone and3-[(cyclopentano-b-pyrrol-2-yl)methylene]-2-indolinone compounds.

[0113] The term “optionally substituted” refers, for example, to abenzene ring that either harbors a hydrogen at a particular position oroptionally harbors another substituent at that position. The term“optionally substituted” refers to other molecules in addition tobenzene. A ring structure, for example can be N-substituted orC-substituted.

[0114] The term “N-substituted” refers to a compound that harborschemical substituents attached to a nitrogen atom in a ring of theindolinone.

[0115] The term “C-substituted” refers to a compound that harborschemical substituents attached to a carbon atom in the indolinone.

[0116] The term “independently selected” refers to a molecule thatharbors one substituent chosen from a group of substituents.

[0117] A preferred embodiment of the invention relates to an indolinonecompound of the following formula,

[0118] where (a) R₁ is selected from the group consisting of,

[0119] (i) hydrogen;

[0120] (ii) alkyl that is optionally substituted with a monocyclic orbicyclic five, six, eight, nine, or ten membered heterocyclic ring,where the ring is optionally substituted with one or more halogen, ortrihalomethyl substituents;

[0121] (iii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents;

[0122] (iv) ketone of formula —CO—R₁₁, where R₁₁ is selected from thegroup consisting of hydrogen, alkyl, or a five or six memberedheterocyclic ring;

[0123] (v) a carboxylic acid of formula —(R₁₂)_(n)—COOH or ester offormula —(R₁₃)_(m)—COO—R₁₄, where R₁₂, R₁₃, and R₁₄ and areindependently selected from the group consisting of alkyl or a five orsix membered heterocyclic ring and n and m are independently 0 or 1;

[0124] (vi) a sulfone of formula —(SO2)—R₁₅, where R₁₅ is selected fromthe group consisting of alkyl or a five or six membered heterocyclicring, where the ring is optionally substituted with an alkyl moiety;

[0125] (vii) -(R₁₆)_(n)-(indole-1-yl) or —(R₁₇)_(m)—CHOH—(R₁₈)p-(indole-1-yl), where the indole moiety is optionally substitutedwith an aldehyde and R₁₆, R₁₇, and R₁₈ are alkyl and n, m, and p areindependently 0 or 1;

[0126] (viii) taken together with a 2′ substituent of the indole ringform a tricyclic moiety, where each ring in the tricyclic moiety is afive or six membered heterocyclic ring;

[0127] (b) R₂, R₃, R_(3′), R₄, R_(4′), R₅, R_(5′), R₆ and R_(6′) areindependently selected from the group consisting of,

[0128] (i) hydrogen;

[0129] (ii) alkyl that is optionally substituted with a monocyclic orbicyclic five, six, eight, nine, or ten membered heterocyclic ring,where the ring is optionally substituted with one or more halogen,aldehyde, or trihalomethyl substituents;

[0130] (iii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents;

[0131] (iv) ketone of formula —CO—R₂₀, where R₂₀ is selected from thegroup consisting of hydrogen, alkyl, or a five or six memberedheterocyclic ring;

[0132] (v) a carboxylic acid of formula —(R₂₁)_(n)—COOH or ester offormula —(R₂₂)—COO—R₂₃, where R₂₁, R₂₂, and R₂₃ and are independentlyselected from the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1;

[0133] (vi) halogen;

[0134] (vii) an alcohol of formula (R₂₄)_(m)—OH or an ether of formula—(R₂₄)_(n)—O—R₂₅, where R₂₄ and R₂₅ are independently selected from thegroup consisting of alkyl and a five or six membered heterocyclic ringand m and n are independently 0 or 1;

[0135] (viii) —NR₂₆R₂₇ where R₂₆ and R₂₇ are independently selected fromthe group consisting of hydrogen, oxygen, alkyl, and a five or sixmembered heterocyclic ring;

[0136] (ix) —NHCOR₂₈, where R₂₈ is selected from the group consisting ofhydroxyl, alkyl, and a five or six membered heterocyclic ring, where thering is optionally substituted with alkyl, halogen, carboxylate, orester;

[0137] (x) —SO2NR₂₉R₃₀, where R₂₉ and R₃₀ are selected from the groupconsisting of hydrogen, oxygen, alkyl, and a five or six memberedheterocyclic ring;

[0138] (xi) any two of R₃, R_(3′), R₄, R_(4′), R₅, R_(5′), R₆, or R_(6′)taken together form a bicyclic or tricyclic hetercyclic moiety fused tothe six membered ring of the indole, where each ring in the multicyclicmoiety is a five or six membered heterocyclic ring;

[0139] (c) R₇, R₈, R₉, and R₁₀ are independently selected from the groupconsisting of,

[0140] (i) hydrogen;

[0141] (ii) alkyl that is optionally substituted with a monocyclic orbicyclic five, six, eight, nine, or ten membered heterocyclic ring,where the ring is optionally substituted with one or more halogen, ortrihalomethyl substituents;

[0142] (iii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents;

[0143] (iv) ketone of formula —CO—R₃₁, where R₃₁ is selected from thegroup consisting of hydrogen, alkyl, or a five or six memberedheterocyclic ring;

[0144] (v) a carboxylic acid of formula —(R₃₂)_(n)—COOH or ester offormula —(R₃₃)_(m)—COO—R₃₄, where R₃₂, R₃₃, and R₃₄ and areindependently selected from the group consisting of alkyl or a five orsix membered heterocyclic ring and n and m are independently 0 or 1;

[0145] (vi) halogen;

[0146] (vii) an alcohol of formula (R₃₅)_(m)—OH or an ether of formula—(R₃₅)_(n)—O—R₃₆, where R₃₅ and R₃₆ are independently chosen from thegroup consisting of alkyl or a five or six membered heterocyclic ringand m and n are independently 0 or 1;

[0147] (viii) —NR₃₇R₃₈, where R₃₇ and R₃₈ are independently selectedfrom the group consisting of hydrogen, oxygen, alkyl, and a five or sixmembered heterocyclic ring;

[0148] (ix) —NHCOR₃₉, where R₃₉ is selected from the group consisting ofhydroxyl, alkyl, and a five or six membered heterocyclic ring, where thering is optionally substituted with alkyl, halogen, carboxylate, orester;

[0149] (x) —SO2NR₄₀R₄₁, where R₄₀ and R₄₁ are selected from the groupconsisting of hydrogen, oxygen, alkyl, and a five or six memberedheterocyclic ring;

[0150] (xi) any two of R₇, R₈, R₉, or R₁₀ taken together form a bicyclicor tricyclic hetercyclic moiety fused to the six membered ring of theindole, where each ring in the multicyclic moiety is a five or sixmembered heterocyclic ring; and

[0151] (d) R₁₁ is hydrogen or alkyl.

[0152] Another preferred embodiment of the invention relates toindolinone compounds of structures VIII and IX, where R₁, R₂, R₃,R_(3′), R₄, R_(4′), R₅, R_(5′), R₆, R_(6′), R₇, R₈, R₉, R₁₀, and R₁₁ arehydrogen.

[0153] In another preferred embodiment, the invention relates tooxidolinone compounds of structures VIII and IX, where R₈ is bromine,chlorine, or NH2 and R₂ R₂, R₃, R_(3′), R₄, R_(4′), R₅, R_(5′), R₆,R_(6′), R₇, R₉, R₁₀, and R₁₁ are hydrogen.

[0154] In yet another preferred, embodiment, the invention relates toindolinone compounds of structures VIII and IX, where R₇ is methyl andR₁, R₂, R₃, R_(3′), R₄, R_(4′), R₅, R_(5′), R₆, R_(6′), R₇, R₉, R₁₀, andR₁₁ are hydrogen.

[0155] In another aspect, the invention features a method ofsynthesizing an indolinone compound, where the method comprises thesteps of:

[0156] (a) reacting an aldehyde of formula X or XI with an oxindol offormula XII,

[0157] where R₁, R₂, R₃, R_(3′), R₄, R_(4′), R₅, R_(5′), R₆, R_(6′), R₇,R₈, R₉, R₁₀, and R₁₁ are described herein; and

[0158] (b) separating the indolinone compound from the aldehyde andoxindole reactants.

[0159] In another aspect, the invention features an indolinone compoundhaving a substituent at the 5 position of the oxindole ring, where thesubstituent at the 5 position of the oxindole ring is selected from thegroup consisting of:

[0160] (a) alkyl that is optionally substituted with a monocyclic orbicyclic five, six, eight, nine, or ten membered heterocyclic ring,where the ring is optionally substituted with one or more halogen, ortrihalomethyl substituents;

[0161] (b) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents;

[0162] (c) a ketone of formula —CO—R₁₀, where R₁₀ is selected from thegroup consisting of hydrogen, alkyl, or a five or six memberedheterocyclic ring;

[0163] (d) a carboxylic acid of formula -(R₁₁)n-COOH or ester of formula—(R₁₂)—COO—R₁₃, where R₁₁, R₁₂, and R₁₃ and are independently selectedfrom the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1;

[0164] (e) halogen;

[0165] (f) an alcohol of formula (R₁₄)_(m)—OH or an ether of formula—(R₁₄)n-O—R₁₅, where R₁₄ and R₁₅ are independently selected from thegroup consisting of alkyl and a five or six membered heterocyclic ringand m and n are independently 0 or 1;

[0166] (g) —NR₁₆R₁₇, where R₁₆ and R₁₇ are independently selected fromthe group consisting of hydrogen, alkyl, and a five or six memberedheterocyclic ring;

[0167] (h) —NHCOR₁₈, where R₁₈ is selected from the group consisting ofalkyl, and a five or six membered heterocyclic ring, where the ring isoptionally substituted with alkyl, halogen, carboxylate, or ester;

[0168] (i) —SO₂NR₁₉R₂₀, where R₁₉ and R₂₀ are selected from the groupconsisting of hydrogen, alkyl, and a five or six membered heterocyclicring;

[0169] (j) any two of R₄, R₅, R₆, or R₇ taken together form a bicyclicor tricyclic hetercyclic moiety fused to the six membered ring of theindole, where each ring in the multicyclic moiety is a five or sixmembered heterocyclic ring.

[0170] A preferred embodiment of the invention relates to a compound ofthe following formula,

[0171] where (a) R₅ is selected from the group consisting of,

[0172] (i) alkyl that is optionally substituted with a monocyclic orbicyclic five, six, eight, nine, or ten membered heterocyclic ring,where the ring is optionally substituted with one or more halogen, ortrihalomethyl substituents;

[0173] (ii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents;

[0174] (iii) a ketone of formula —CO—R₁₀, where R₁₀ is selected from thegroup consisting of hydrogen, alkyl, or a five or six memberedheterocyclic ring;

[0175] (iv) a carboxylic acid of formula —(R₁₁)n-COOH or ester offormula —(R₁₂)—COO—R₁₃, where R₁₁, R₁₂, and R₁₃ and are independentlyselected from the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1;

[0176] (v) halogen;

[0177] (vi) an alcohol of formula (R₁₄)_(m)—OH or an ether of formula—(R₁₄)_(n)—O—R₁₅, where R₁₄ and R₁₅ are independently selected from thegroup consisting of alkyl and a five or six membered heterocyclic ringand m and n are independently 0 or 1;

[0178] (vii) —NR₁₆R₁₇, where R₁₆ and R₁₇ are independently selected fromthe group consisting of hydrogen, alkyl, and a five or six memberedheterocyclic ring;

[0179] (viii) —NHCOR₁₈, where R₁₈ is selected from the group consistingof alkyl, and a five or six membered heterocyclic ring, where the ringis optionally substituted with alkyl, halogen, carboxylate, or ester;

[0180] (ix) —SO₂NR₁₉R₂₀, where R₁₉ and R₂₀ are selected from the groupconsisting of hydrogen, alkyl, and a five or six membered heterocyclicring;

[0181] (x) any two of R₄, R₅, R₆, or R₇ taken together form a bicyclicor tricyclic hetercyclic moiety fused to the six membered ring of theoxindole, where each ring in the multicyclic moiety is a five or sixmembered heterocyclic ring;

[0182] (b) R₁ is selected from the group consisting of a five, six,eight, nine, and ten membered monocyclic or bicyclic heterocyclic ring,where the ring is optionally substituted with one or more substituentsselected from the group consisting of

[0183] (i) hydrogen and alkyl that is optionally substituted with amonocyclic or bicyclic five, six, eight, nine, or ten memberedheterocyclic ring, where the ring is optionally substituted with one ormore halogen, or trihalomethyl substituents;

[0184] (ii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents;

[0185] (iii) a ketone of formula —CO—R₂₁, where R₂₁ is selected from thegroup consisting of hydrogen, alkyl, or a five or six memberedheterocyclic ring;

[0186] (iv) a carboxylic acid of formula —(R₂₂)_(n)—COOH or ester offormula —(R₂₃)—COO—R₂₄, where R₂₂, R₂₃, and R₂₄ and are independentlyselected from the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1;

[0187] (v) halogen;

[0188] (vi) an alcohol of formula (R₂₅)m-OH or an ether of formula—(R₂₅)_(n)—O—R₂₆, where R₂₅ and R₂₆ are independently selected from thegroup consisting of alkyl and a five or six membered heterocyclic ringand m and n are independently 0 or 1;

[0189] (vii) —NR₂₇R₂₈, where R₂₇ and R₂₈ are independently selected fromthe group consisting of hydrogen, alkyl, and a five or six memberedheterocyclic ring;

[0190] (viii) —NHCOR₂₉, where R₂₉ is selected from the group consistingof alkyl, and a five or six membered heterocyclic ring, where the ringis optionally substituted with alkyl, halogen, carboxylate, or ester;

[0191] (ix) —SO₂NR₃₀R₃₁, where R₃₀ and R₃₁ are selected from the groupconsisting of hydrogen, alkyl, and a five or six membered heterocyclicring;

[0192] (c) R₄, R₆, and R₇ are independently selected from the groupconsisting of,

[0193] (i) hydrogen and alkyl that is optionally substituted with amonocyclic or bicyclic five, six, eight, nine, or ten memberedheterocyclic ring, where the ring is optionally substituted with one ormore halogen, or trihalomethyl substituents;

[0194] (ii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents;

[0195] (iii) a ketone of formula —CO—R₃₂, where R₃₂ is selected from thegroup consisting of hydrogen, alkyl, or a five or six memberedheterocyclic ring;

[0196] (iv) a carboxylic acid of formula —(R₃₃)n-COOH or ester offormula —(R₃₄)—COO—R₃₅, where R₃₃, R₃₄, and R₃₅ and are independentlyselected from the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1;

[0197] (v) halogen;

[0198] (vi) an alcohol of formula (R₃₆)m-OH or an ether of formula—(R₃₆)_(n)—O—R₃₇, where R₃₆ and R₃₇ are independently selected from thegroup consisting of alkyl and a five or six membered heterocyclic ringand m and n are independently 0 or 1;

[0199] (vii) —NR₃₈R₃₉, where R₃₈ and R₃₉ are independently selected fromthe group consisting of hydrogen, alkyl, and a five or six memberedheterocyclic ring;

[0200] (viii) —NHCOR₄₀, where R₄₀ is selected from the group consistingof alkyl, and a five or six membered heterocyclic ring, where the ringis optionally substituted with alkyl, halogen, carboxylate, or ester;

[0201] (ix) —SO₂NR₄₁R₄₂, where R₄₁ and R₄₂ are selected from the groupconsisting of hydrogen, alkyl, and a five or six membered heterocyclicring; and

[0202] (d) R₂ is hydrogen or alkyl.

[0203] In preferred embodiments of the invention shown in structure XIIIabove one or more of R₁, R₄, R₅, R₆, or R₇ are a heterocyclic ring.Preferred heterocycles of the invention are described herein.

[0204] Another preferred embodiment of the invention shown in structureXIII above is an indolinone compound, where R₁ is(3,5-dimethylpyrrol)-2-yl, R₅ is —COOH, and R₂, R₄, R₆, and R₇ arehydrogen.

[0205] Another preferred embodiment of the invention shown in structureXIII above is an indolinone compound, where R₁ is(3,5-diethylpyrrol)-2-yl, R₅ is —COOH, and R₂, R₄, R₆, and R₇ arehydrogen.

[0206] Another preferred embodiment of the invention shown in structureXIII above is an indolinone compound, where R₁ is(3,5-diisopropylpyrrol)-2-yl, R₅ is —COOH, and R₂, R₄, R₆, and R₇ arehydrogen.

[0207] Another preferred embodiment of the invention shown in structureXIII above is an indolinone compound, where R₁ is(3,5-dimethylpyrrol)-2-yl, R₅ is —(CH₂)₂COOH, and R₂, R₄, R₆, and R₇ arehydrogen.

[0208] Another preferred embodiment of the invention shown in structureXIII above is an indolinone compound, where R₁ is(5-methylthiophene)-2-yl, R₅ is —COOH, and R₂, R₄, R₆, and R₇ arehydrogen.

[0209] In another aspect, the invention features a method ofsynthesizing an indolinone compound, where the method comprises thesteps of:

[0210] (a) reacting an aldehyde of formula XIV with an oxindole offormula XV,

[0211] where R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, and R₁₁ are asdescribed herein; and

[0212] (b) separating the indolinone compound from the aldehyde andoxindole reactants.

[0213] In another aspect, the invention features an indolinone compoundhaving a substituent at the 3 position of the oxindole ring, where thesubstituent at the 3 position of the oxindole ring is selected from thegroup consisting of five-membered or six-membered heterocyclic rings.The oxindolonine is further substituted with groups enhancinghydrosolubility as set forth below.

[0214] A preferred embodiment of the invention relates to a compound ofthe following formula:

[0215] wherein

[0216] (a) A is a five membered heterocyclic ring selected from thefollowing group consisting of thiophene, pyrrole, pyrazole, imidazole,1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole,isothiazole, furan, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole,1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole,1,2,3,5-thiatriazole, and tetrazole

[0217] (b) m is zero, 1, or 2;

[0218] (c) R₁ is hydrogen, C₁—C₆ alkyl or C₂—C₆ alkanoyl;

[0219] (d) one of R₂ and R₃ independently is hydrogen and the other is asubstituent selected from:

[0220] (1) a C₁—C₆ alkyl group substituted by 1, 2 or 3 hydroxy groups;

[0221] (2) SO₃R₄ in which R₄ is hydrogen or C₁—C₆ alkyl unsubstituted orsubstituted by 1, 2 or 3 hydroxy groups;

[0222] (3) SO₂NHR₅ in which R₅ is as R₄ defined above or a—(CH₂)_(n)—N(C₁—C₆ alkyl)₂ group in which n is 2 or 3;

[0223] (4) COOR₆ in which R₆ is C₁—C₆ alkyl unsubstituted or substitutedby phenyl or by 1, 2 or 3 hydroxy groups or phenyl;

[0224] (5) CONHR₇ in which R₇ is hydrogen, phenyl or C₁—C₆ alkylsubstituted by 1, 2 or 3 hydroxy groups or by phenyl;

[0225] (6) NHSO₂R₈ in which R₈ is C₁—C₆ alkyl or phenyl unsubstituted orsubstituted by halogen or by C₁—C₄ alkyl;

[0226] (7) N(R₉)₂, NHR₉ or OR₉ wherein R₉ is C₂—C₆ alkyl substituted by1, 2 or 3 hydroxy groups;

[0227] (8) NHCOR₁₀, OOCR₁₀ or CH₂OOCR₁₀ in which R₁₀ is C₁—C₆ alkylsubstituted by 1, 2 or 3 hydroxy groups;

[0228] (9) NHCONH₂; NH—C(NH₂)═NH; C(NH₂)═NH; CH₂NHC(NH₂)═NH; CH₂NH₂;OPO(OH)₂; CH₂OPO(OH)₂; PO(OH)₂; or a

[0229] group wherein X is selected from the group consisting of CH₂,SO₂, CO, or NHCO(CH₂)_(p) in which p is 1, 2, or 3 and Z is CH2, O orN—R₁₁, in which R₁₁ is hydrogen or is as R₉ defined above.

[0230] The term “alkanoyl” refers to a chemical moiety with formula—(R)_(n)—CO—R′, where R and R′ are selected from the group consisting ofalkyl or aryl and n is 0 or 1.

[0231] Inhibitors of protein kinase catalytic activity are known in theart. Small molecule inhibitors typically block the binding of substratesby tightly interacting with the protein kinase active-site. Indolinonecompounds, for example, can bind to the active-site of a protein kinaseand inhibit the molecule effectively, as measured by inhibitionconstants on the order of 10⁻⁶ M.

[0232] A preferred embodiment of the invention relates to anhydrosoluble indolinone compound that inhibits the catalytic activity ofa FLK protein kinase. The indolinone preferably inhibits the catalyticactivity of the FLK protein kinase with an IC₅₀ less than 50 μM, morepreferably with an IC₅₀ less than 5 μM, and most preferably with an IC₅₀less than 0.5 μM.

[0233] In another aspect, the invention features a method ofsynthesizing a hydrosoluble indolinone compound, where the methodcomprises the steps of:

[0234] (a) reacting an aldehyde of formula XVI with an oxindole offormula XVII,

[0235] where

[0236] (a) A is a five or six membered ring comprised of atoms selectedfrom the group consisting of oxygen, carbon, sulfer and nitrogen

[0237] (b) m is zero, 1, or 2;

[0238] (c) R₁ is hydrogen, C₁—C₆ alkyl or C₂—C₆ alkanoyl;

[0239] (d) one of R₂ and R₃ independently is hydrogen and the other is asubstituent selected from:

[0240] (1) a C₁—C₆ alkyl group substituted by 1, 2 or 3 hydroxy groups;

[0241] (2) SO₃R₄ in which R₄ is hydrogen or C₁—C₆ alkyl unsubstituted orsubstituted by 1, 2 or 3 hydroxy groups;

[0242] (3) SO₂NHR₅ in which R₅ is as R₄ defined above or a—(CH₂)_(n)—N(C₁—C₆ alkyl)₂ group in which n is 2 or 3;

[0243] (4) COOR₆ in which R₆ is C₁—C₆ alkyl unsubstituted or substitutedby phenyl or by 1, 2 or 3 hydroxy groups or phenyl;

[0244] (5) CONHR₇ in which R₇ is hydrogen, phenyl or C₁—C₆ alkylsubstituted by 1, 2 or 3 hydroxy groups or by phenyl;

[0245] (6) NHSO₂R₈ in which R₈ is C₁—C₆ alkyl or phenyl unsubstituted orsubstituted by halogen or by C₁—C₄ alkyl;

[0246] (7) N(R₉)₂, NHR₉ or OR₉ wherein R₉ is C₂—C₆ alkyl substituted by1, 2 or 3 hydroxy groups;

[0247] (8) NHCOR₁₀, OOCR₁₀ or CH₂OOCR₁₀ in which R₁₀ is C₁—C₆ alkylsubstituted by 1, 2 or 3 hydroxy groups;

[0248] (9) NHCONH₂; NH—C(NH₂)═NH; C(NH)═NH; ₂ CH₂NHC(NH₂)═NH; CH₂NH₂;OPO(OH)₂; CH₂OPO(OH)₂; PO(OH)₂; or a

[0249] group wherein X is selected from the group consisting of CH₂,SO₂, CO, or NHCO(CH₂)_(p) in which p is 1,2, or 3 and Z is CH2, O orN—R₁₁ in which R₁₁ is hydrogen or is as R₉ defined above; and

[0250] (b) separating the indolinone compound from the aldehyde andoxindole reactants.

[0251] Another aspect of the invention features a pharmaceuticalcomposition comprising an oxidolinone compound of the invention and aphysiologically acceptable carrier or diluent.

[0252] In the embodiments set forth below, several preferred subclassesof compounds having activity against Flk are set forth. Thus, in oneembodiment, the invention provides compounds having the formula:

[0253] wherein

[0254] R₁ is hydrogen or alkyl (preferably lower alkyl, more preferablymethyl);

[0255] R₂ is oxygen or sulfur;

[0256] R₃ is hydrogen or methyl;

[0257] R₄, R₅, R₆, and R₇ are each independently selected from the groupconsisting of hydrogen (preferably at least two or three of R₄, R₅, R₆and R₇ are hydrogen), alkyl (preferably lower alkyl, more preferablymethyl), halogen, NO₂, and NRR′;

[0258] R_(2′), R_(3′), R_(4′), R_(5′), and R_(6′) are each independentlyselected from the group consisting of hydrogen, alkyl, halogen, NO₂,NRR′ (where taken together NRR¹ may form a five or six membernon-aromatic heterocyc optionally substituted with COH), OH, ORNRR¹, andOR;

[0259] R is hydrogen, alkyl or aryl; and

[0260] R′ is hydrogen, alkyl or aryl.

[0261] In another embodiment, the invention provides compounds havingthe formula:

[0262] wherein

[0263] R₁ is hydrogen or alkyl (preferably lower alkyl, more preferablymethyl);

[0264] R₂ is oxygen or sulfer;

[0265] R₃ is hydrogen or methyl;

[0266] R₄, R₅, R₆, and R₇ are each independently selected from the groupconsisting of hydrogen, alkyl (preferably lower alkyl, more preferablymethyl), halogen, and NRR′;

[0267] R_(2′), R_(3′), R_(4′), and R_(5′), are each independentlyselected from the group consisting of hydrogen, alkyl, halogen, and(alkyl)_(n)CO₂R;

[0268] R is hydrogen, alkyl or aryl; and

[0269] R′ is hydrogen, alkyl or aryl.

[0270] In another embodiment, the invention provides compounds havingthe formula:

[0271] wherein

[0272] R₁, R₂, and R₃, are each independently selected from the groupconsisting of hydrogen, alkyl, halogen, and (alkyl)_(n)CO₂R;

[0273] R₄, R₅, R₆, and R₇ are each independently selected from the groupconsisting of hydrogen, alkyl (preferably lower alkyl, more preferablymethyl), halogen, and NRR′;

[0274] R₈ and R₉ are independently hydrogen or alkyl;

[0275] R is hydrogen, alkyl or aryl; and

[0276] R′ is hydrogen, alkyl or aryl.

[0277] In another embodiment, the invention provides compounds havingthe formula:

[0278] wherein

[0279] R_(1′), R_(2′), R_(3′), R_(4′) and R₇ are each independentlyselected from the group consisting of hydrogen, alkyl (preferably loweralkyl, more preferably methyl), halogen and NRR′;

[0280] R₈ and R₉ are independently hydrogen or alkyl;

[0281] R is hydrogen, alkyl or aryl; and

[0282] R′ is hydrogen, alkyl or aryl.

[0283] In another aspect, the invention features a method ofsynthesizing an indolinone compound, where the method comprises thesteps of:

[0284] (a) reacting an appropriate aldehyde with an appropriateoxindole,

[0285] (b) separating the indolinone compound from the aldehyde andoxindole reactants.

[0286] In another aspect, the invention features an indolinone compound,salt, ester, amide, prodrug, isomer, or metabolite thereof thatmodulates the catalytic activity of a protein kinase.

[0287] The term “modulates” refers to the ability of a compound toalters the catalytic activity of a protein kinase. A modulatorpreferably activates the catalytic activity of a protein kinase, morepreferably activates or inhibits the catalytic activity of a proteinkinase depending on the concentration of the compound exposed to theprotein kinase, or most preferably inhibits the catalytic activity of aprotein kinase.

[0288] The term “protein kinase” defines a class of proteins thatregulate a variety of cellular functions. Protein kinases regulatecellular functions by reversibly phosphorylating protein substrateswhich thereby changes the conformation of the substrate protein. Theconformational change modulates catalytic activity of the substrate orits ability to interact with other binding partners.

[0289] The term “catalytic activity”, in the context of the invention,defines the rate at which a protein kinase phosphorylates a substrate.Catalytic activity can be measured, for example, by determining theamount of a substrate converted to a product as a function of time.Phosphorylation of a substrate occurs at the active-site of a proteinkinase. The active-site is normally a cavity in which the substratebinds to the protein kinase and is phosphorylated.

[0290] A preferred embodiment of the invention relates to an indolinonecompound that inhibits the catalytic activity of a FLK protein kinase.The indolinone preferably inhibits the catalytic activity of the FLKprotein kinase with an IC50 less than 50 μM, more preferably with anIC50 less than 5 μM, and most preferably with an IC50 less than 0.5 μM.

[0291] The term “FLK” refers to a protein kinase that phosphorylatesprotein substrates on tyrosine residues. The FLK protein kinaseregulates cellular functions in response to the VEGF growth factor.These cellular functions include, but are not limited to, cellularproliferation, and in particular, blood vessel proliferation in tissues.

[0292] The term “IC₅₀”, in the context of the invention, refers to aparameter that describes the concentration of a particular indolinonerequired to inhibit 50% of the FLK protein kinase catalytic activity.The IC₅₀ parameter can be measured using an assay described herein andby varying the concentration of a particular indolinone compound.

[0293] Another aspect of the invention features a pharmaceuticalcomposition comprising, consisting essentially of, or consisting of anindolinone compound, salt, ester, amide, prodrug, isomer, or metabolitethereof of the invention and a physiologically acceptable carrier ordiluent.

[0294] The term “pharmaceutical composition” refers to a mixture of anindolinone compound of the invention with other chemical components,such as diluents or carriers. The pharmaceutical composition facilitatesadministration of the compound to an organism. Multiple techniques ofadministering a compound exist in the art including, but not limited to,oral, injection, aerosol, parenteral, and topical administration.Pharmaceutical compositions can also be obtained by reacting compoundswith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and thelike.

[0295] The term “physiologically acceptable” defines a carrier ordiluent that does not cause significant irritation to an organism anddoes not abrogate the biological activity and properties of thecompound.

[0296] The term “carrier” defines a chemical compound that facilitatesthe incorporation of a compound into cells or tissues. For exampledimethyl sulfoxide (DMSO) is a commonly utilized carrier as itfacilitates the uptake of many organic compounds into the cells ortissues of an organism.

[0297] The term “diluent” defines chemical compounds diluted in waterthat will dissolve the compound of interest as well as stabilize thebiologically active form of the compound. Salts dissolved in bufferedsolutions are utilized as diluents in the art. One commonly usedbuffered solution is phosphate buffered saline because it mimics thesalt conditions of human blood. Since buffer salts can control the pH ofa solution at low concentrations, a buffered diluent rarely modifies thebiological activity of a compound.

[0298] Another aspect of the invention features a method of preventingor treating an abnormal condition in an organism. The abnormal conditionis associated with an aberration in a signal transduction pathwaycharacterized by an interaction between a protein kinase and a naturalbinding partner. The method comprises the following steps: (a)administering a compound of the invention to an organism; and (b)promoting or disrupting the abnormal interaction.

[0299] The term “preventing” refers to a method of barring the organismfrom acquiring the abnormal condition.

[0300] The term “treating” refers to a method of alleviating orabrogating the abnormal condition in the organism.

[0301] The term “organism” relates to any living entity comprised of atleast one cell. An organism can be as simple as one eukaryotic cell oras complex as a mammal.

[0302] The term “abnormal condition” refers to a function in the cellsor tissues of an organism that deviates from their normal functions inthat organism. An abnormal condition can relate to cell proliferation,cell differentiation, or cell survival.

[0303] Aberrant cell proliferative conditions include cancers such asfibrotic and mesangial disorders, abnormal angiogenesis andvasculogenesis, wound healing, psoriasis, diabetes mellitus, andinflammation.

[0304] Aberrant differentiation conditions include, but are not limitedto neurodegenerative disorders, slow wound healing rates, and tissuegrafting techniques.

[0305] Aberrant cell survival conditions relate to conditions in whichprogrammed cell death (apoptosis) pathways are activated or abrogated. Anumber of protein kinases are associated with the apoptosis pathways.Aberrations in the function of any one of the protein kinases could leadto cell immortality or premature cell death.

[0306] Cell proliferation, differentiation, and survival are phenomenasimply measured by methods in the art. These methods can involveobserving the number of cells or the appearance of cells under amicroscope with respect to time (days).

[0307] The term “administering” relates to a method of incorporating acompound into cells or tissues of an organism. The abnormal conditioncan be prevented or treated when the cells or tissues of the organismexist within the organism or outside of the organism. Cells existingoutside the organism can be maintained or grown in cell culture dishes.For cells harbored within the organism, many techniques exist in the artto administer compounds, including (but not limited to) oral,parenteral, dermal, injection, and aerosol applications. For cellsoutside of the organism, multiple techniques exist in the art toadminister the compounds, including (but not limited to) cellmicroinjection techniques, transformation techniques, and carriertechniques.

[0308] The aberrant condition can also be prevented or treated byadministering a group of cells having an aberration in a signaltransduction process to an organism. The effect of administering acompound on organism function can then be monitored. The art containsmultiple methods of introducing a group of cells to an organism as wellas methods of administering a compound to an organism. The organism ispreferably a frog, more preferably a mouse, rat, rabbit, guinea pig, orgoat, and most preferably a monkey or ape.

[0309] The term “signal transduction pathway” refers to the moleculesthat propagate an extracellular signal through the cell membrane tobecome an intracellular signal. This signal can then stimulate acellular response. The polypeptide molecules involved in signaltransduction processes are typically receptor and non-receptor proteinkinases, receptor and non-receptor protein phosphatases, nucleotideexchange factors, and transcription factors.

[0310] The term “aberration”, in conjunction with a signal transductionprocess, refers to a protein kinase that is over- or under-expressed inan organism, mutated such that its catalytic activity is lower or higherthan wild-type protein kinase activity, mutated such that it can nolonger interact with a natural binding partner, is no longer modified byanother protein kinase or protein phosphatase, or no longer interactswith a natural binding partner.

[0311] The term “natural binding partner” refers to a polypeptide thatnormally binds to the intracellular region of a protein kinase in acell. These natural binding partners can play a role in propagating asignal in a protein kinase signal transduction process. The naturalbinding partner can bind to a protein kinase intracellular region withhigh affinity. High affinity represents an equilibrium binding constanton the order of 10⁻⁶ M or less. However, a natural binding partner canalso transiently interact with a protein kinase intracellular region andchemically modify it. Protein kinase natural binding partners are chosenfrom a group consisting of, but not limited to, src homology 2 (SH2) or3 (SH3) domains, other phosphoryl tyrosine binding (PTB) domains, andother protein kinases or, protein phosphatases. The term “promoting ordisrupting the abnormal interaction” refers to a method that can beaccomplished by administering a compound of the invention to cells ortissues in an organism. A compound can promote an interaction between aprotein kinase and natural binding partners by forming favorableinteractions with multiple amino acids at the complex interface.Alternatively, a compound can inhibit an interaction between a proteinkinase and natural binding partners by compromising favorableinteractions formed between amino acids at the complex interface.

[0312] A preferred embodiment of the invention relates to the method oftreating an abnormal condition in an organism, where the organism is amammal.

[0313] The term “mammal” refers preferably to such organisms as mice,rats, rabbits, guinea pigs, and goats, more preferably to monkeys andapes, and most preferably to humans.

[0314] Another preferred embodiment of the invention relates to a methodof treating or preventing an abnormal condition associated with the FLKprotein kinase.

[0315] Another preferred embodiment of the invention relates to anindolinone compound that inhibits the catalytic activity of a plateletderived growth factor protein kinase. The indolinone preferably inhibitsthe catalytic activity of the platelet derived growth factor proteinkinase with an IC₅₀ less than 50 μM, more preferably with an IC₅₀ lessthan 5 μM, and most preferably with an IC₅₀ less than 0.5 μM.

[0316] The term “platelet derived growth factor” refers to a proteinkinase that phosphorylates substrates on tyrosine residues. The plateletderived growth factor protein kinase regulates cellular functions inresponse to the PDGF growth factor. These cellular functions include,but are not limited to, cellular proliferation.

[0317] The chemical formulae referred herein may exhibit the phenomenaof tautomerism or structural isomerism. For example, the compoundsdescribed herein may be adopt a cis or trans conformation about thedouble bond connecting the indolinone 3-substituent to the indolinonering, or may be mixtures of cis and trans isomers. As the formulaedrawing within this specification can only represent one possibletautomeric or structural isomeric form, it should be understood that theinvention encompasses any tautomeric or structural isomeric form, ormixtures thereof, which possesses the ability to regulate, inhibitand/or modulate tyrosine kinase signal transduction or cellproliferation and is not limited to any one tautomeric or structuralisomeric form utilized within the formulae drawing.

[0318] In addition to the above-described compounds, the invention isfurther directed, where applicable, to solvated as well as unsolvatedforms of the compounds (e.g. hydrated forms) having the ability toregulate and/or modulate cell proliferation.

[0319] The compounds described herein may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Suitable processes are illustrated in the examples. Necessarystarting materials may be obtained by standard procedures of organicchemistry.

[0320] An individual compound's relevant activity and efficacy as anagent to affect receptor tyrosine kinase mediated signal transductionmay be determined using available techniques. Preferentially, a compoundis subjected to a series of screens to determine the compound's abilityto modulate, regulate and/or inhibit cell proliferation. These screens,in the order in which they are conducted, include biochemical assays,cell growth assays and in vivo experiments.

[0321] The summary of the invention described above is not limiting andother features and advantages of the invention will be apparent from thefollowing detailed description of the invention, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS AND TABLES

[0322]FIG. 1 shows illustrative type A oxindoles.

[0323]FIG. 2 shows illustrative type B aldehydes.

[0324] Table 1 depicts examples of compounds of the invention. The tableillustrates the molecular structure of each indolinone, the molecularweight of the compound, and the chemical formula of the compound.

[0325] Table 2 depicts the biological activity of select compounds ofthe invention. Listed are the chemical structure of the compound withIC₅₀ values measured in FLK-1 biological inhibition assays.

[0326] Table 3 shows preferred indole based aldehydes that can be usedin the present invention.

[0327] Table 4 shows preferred oxindoles that can be used in the presentinvention.

[0328] Table 5 depicts examples of compounds of the invention. The tableillustrates the molecular structure of each indolinone, the molecularweight of the compound, and the chemical formula of the compound.

[0329] Tables 6 and 7 depicts the biological activity of selectcompounds of the invention. Listed are the chemical structure of thecompound with IC₅₀ values measured in FLK-1 and platelet derived growthfactor protein kinase (PDGFR) biological inhibition assays.

[0330] Table 8 depicts examples of compounds of the invention. The tableillustrates the molecular structure of exemplary indolinones and thebiological activity of select compounds of the invention. Listed are thechemical structure of the compound with IC₅₀ values measured in FLK-1biological inhibition assays.

[0331] Table 9 lists exemplary compounds of the invention.

[0332] Table 10 shows FLK activity data for illustrative compounds ofthe invention.

[0333] Table 11 shows type A oxindols.

[0334] Table 12 shows type B aldehydes.

[0335] Table 13 shows the names of several indolinone compounds of thepresent invention.

[0336] Table 14 shows kinase data for the compounds listed in Table 13as determined using the assays described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0337] The invention is directed in part towards designing proteinkinase inhibitors that obliterate tumors by severing their sources ofsustenance. The inhibitors are designed to specifically bind proteinkinases over-expressed in the vasculature that supply tumors withsustenance. One such protein kinase target is FLK-1, which isover-expressed in the proliferating endothelial cells of a growingtumor, but not in the surrounding quiescent endothelial cells. Plate etal., 1992, Nature 359:845-848.

[0338] FLK-1 is activated upon binding VEGF, a strong regulator forendothelial cell proliferation as well as normal and pathologicalangiogenesis. Klagsburn and Soker, 1993, Current Biology 3:699-702.Thus, compounds that specifically inhibit the FLK protein kinase arepotential anti-cancer agents as they may decrease the vasculature thatnourishes tumors. These inhibitors will most likely result in minimizingand even obliterating solid tumors. In addition, compounds thatspecifically inhibit FLK will potentially represent a new generation ofcancer therapeutics as they will most likely cause few side effects.These potential properties are a welcome improvement over the currentlyutilized cancer therapeutics that cause multiple side effects anddeleteriously weaken patients.

[0339] Synthesis of Indolinone Compounds

[0340] The indolinone compounds of the invention are synthesized byreacting an aldehyde with an oxindol as shown in the examples providedherein. Descriptions of methods for synthesizing indolinone compoundsare provided in the examples described herein. The examples fullydescribe the solvents, temperatures, separation techniques, and otherconditions utilized for the invention. Other synthetic techniques, suchas those described in International patent publications WO 96/22976,published Aug. 1, 1996 by Ballinari et al., and WO 96/40116, publishedDec. 19, 1996 by Tang et al. may also be used or adapted by thoseskilled in the art to make the compounds of the present invention.Descriptions of the methods used to specifically synthesize theindolinone compounds of the invention, are disclosed herein.

[0341] Biological Activity of Indolinone Compounds

[0342] Indolinone compounds of the invention can be tested for theirability to activate or inhibit protein kinases in biological assays. Themethods used to measure indolinone modulation of protein kinase functionare described herein. Indolinone compounds of the invention were testedfor their ability to inhibit the FLK protein kinase. The biologicalassay and results of these inhibition studies are reported herein.

[0343] Target Diseases to be Treated by Indolinone Compounds

[0344] Protein kinases are essential regulatory molecules that control avariety of cellular functions. For this reason, any alteration in thefunction of a protein kinase can cause an abnormal condition in anorganism. One of the many functions controlled by protein kinases iscell proliferation.

[0345] Alterations in the function of a protein kinase that normallyregulates cell proliferation can lead to enhanced or decreased cellproliferative conditions evident in certain diseases. Aberrant cellproliferative conditions include cancers such as fibrotic and mesangialdisorders, abnormal angiogenesis and vasculogenesis, wound healing,psoriasis, restenosis, diabetes mellitus, and inflammation.

[0346] Fibrotic disorders and mesangial cell proliferative disorders aredescribed in International Patent Publication No. WO 96/40116, publishedDec. 19, 1996 by Tang et al.

[0347] Angiogenic and vasculogenic disorders result from excessproliferation of blood vessels. Blood vessel proliferation is necessaryin a variety of normal physiological processes such as embryonicdevelopment, corpus luteum formation, wound healing and organregeneration. However, blood vessel proliferation is also essential incancer tumor development. Other examples of blood vessel proliferativedisorders include arthritis, where new capillary blood vessels invadethe joint and destroy cartilage. In addition, blood vessel proliferativediseases include ocular diseases, such as diabetic retinopathy, wherenew capillaries in the retina invade the vitreous, bleed and causeblindness. Conversely, disorders related to the shrinkage, contractionor closing of blood vessels, such as restenosis, are also implicated inadverse regulation of RPKs or RPPs.

[0348] Moreover, vasculogenesis and angiogenesis are associated with thegrowth of malignant solid tumors and metastasis. A vigorouslygrowing-cancer tumor requires a nutrient and oxygen rich blood supply tocontinue growing. As a consequence, an abnormally large number ofcapillary blood vessels often grow in concert with the tumor and act assupply lines to the tumor. In addition to supplying nutrients to thetumor, the new blood vessels embedded in a tumor provide a gateway fortumor cells to enter the circulation and metastasize to distant sites inthe organism. Folkman, 1990, J. Natl. Cancer Inst. 82:4-6.

[0349] Angiogenic and vasculogenic disorders are closely linked to theFLK protein kinase. FLK-1 is activated upon binding VEGF, a strongregulator for endothelial cell proliferation as well as normal andpathological angiogenesis. Klagsburn and Soker, 1993, Current Biology3:699-702. Thus, compounds that specifically inhibit the FLK proteinkinase are potential anti-cancer agents as they may decrease thevasculature that nourishes tumors. These inhibitors will most likelyresult in minimizing and even obliterating solid tumors. In addition,compounds that specifically inhibit FLK will potentially represent a newgeneration of cancer therapeutics as they will most likely cause fewside effects. These potential properties are a significant improvementover the currently utilized cancer therapeutics that cause multiple sideeffects and deleteriously weaken patients.

[0350] In addition to cell proliferation, some RPKs and RPPs regulatethe penultimate cellular functions, cell survival and cell death. Glialderived growth factor (GDNF) activates c-ret, for example, by bringingmultiple c-ret receptors together into close proximity and promotingcross phosphorylation of the intracellular regions. Signal transductionmolecules that form a complex with c-ret as a result of these phosphorylmoieties, such as grb-2, sos, ras, and raf, propagate a signal in thecell that promotes neural survival. Thus, compounds that promote theinteractions of these stimulatory molecules of c-ret would enhance theactivity of c-ret. Alternatively, protein phosphatases can remove thephosphoryl moieties placed on the intracellular region of c-ret inresponse to GDNF, and thus inhibit the signaling capability of c-ret.Thus compounds that inhibit phosphatases of c-ret will enhance thesignaling capacity of c-ret. In the context of the present invention,the c-ret protein kinase could be activated by indolinone compounds thatare modified with substituents, particularly at the 5 position of theoxindole ring.

[0351] c-ret is implicated in the development and survival of enteric,synaptic, and sensory neurons and neurons of the renal system uponstimulation by GDNF. Lack of function mutations in c-ret can lead toHirschsprung's disease, for example, which manifests itself as adecrease in intestinal tract innervation in patients. Thus, compoundsthat activate c-ret are potential therapeutic agents for the treatmentof neurodegenerative disorders, including, but not limited to,Hirschsprung's disease, Parkinson's disease, Alzheimer's disease, andamyotrophic lateral sclerosis. Compounds that inhibit c-ret function arepossible anti-cancer agents as over-expression of ret in cells isimplicated in cancers, such as cancer of the thyroid.

[0352] Pharmaceutical Compositions and Administration of IndolinoneCompounds

[0353] Methods of preparing pharmaceutical formulations of thecompounds, methods of determining the amounts of compounds to beadministered to a patient, and modes of administering compounds to anorganism are disclosed in International Patent Publication No. WO96/22976, published Aug. 1, 1996 by Ballinari et al., which isincorporated herein by reference in its entirety, including anydrawings. Those skilled in the art will appreciate that suchdescriptions are applicable to the present invention and can be easilyadapted to it. The mechanism of such action and possible uses for suchcompounds are described in International Patent Publication WO 96/40116,published Dec. 19, 1996 by Tang et al.

[0354] The compounds described herein can be administered to a humanpatient per se, or in pharmaceutical compositions where it is mixed withsuitable carriers or excipient(s). Techniques for formulation andadministration of the compounds of the instant application may be foundin “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton,Pa., latest edition or in International Patent Publication No. WO96/40116, published Dec. 19, 1996 by Tang et al.

[0355] Effective Dosage

[0356] Pharmaceutical compositions suitable for use in the presentinvention include compositions wherein the active ingredients arecontained in an amount effective to achieve its intended purpose. Morespecifically, a therapeutically effective amount means an amount ofcompound effective to prevent, alleviate or ameliorate symptoms ofdisease or prolong the survival of the subject being treated.Determination of a therapeutically effective amount is well within thecapability of those skilled in the art, especially in light of thedetailed disclosure provided herein and in International PatentPublication No. WO 96/40116, published Dec. 19, 1996 by Tang et al.

[0357] Packaging

[0358] The compositions may, if desired, be presented in a pack ordispenser device which may contain one or more unit dosage formscontaining the active ingredient according to the description providedin International Patent Publication No. WO 96/40116, published Dec. 19,1996 by Tang et al.

EXAMPLES

[0359] The examples below are not limiting and are merely representativeof various aspects and features of the present invention. The examplesdemonstrate methods of synthesizing indolinone compounds of theinvention. The examples also demonstrate the specificity as well as thepotency with which these compounds inhibit protein kinase function incells.

Example 1

[0360] Compound Synthesis

[0361] The compounds of the present invention may be synthesizedaccording to known techniques such as those described in InternationalPatent Publication No. WO 96/40116, published Dec. 19, 1996 by Tang etal. The following represent preferred methods for synthesizing thecompounds of the claimed invention.

[0362] (a) Preparation of 4-Methyl-2-oxindole. Diethyl oxalate (30 mL)in 20 mL of dry ether was added with stirring to 19 g of potassiumethoxide suspended in 50 mL of dry ether. The mixture was cooled in anice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowlyadded. The thick dark red mixture was heated to reflux for 0.5 hr,concentrated to a dark red solid, and treated with 10% sodium hydroxideuntil almost all of the solid dissolved. The dark red mixture wastreated with 30% hydrogen peroxide until the red color changed toyellow. The mixture was treated alternatively with 10% sodium hydroxideand 30% hydrogen peroxide until the dark color was no longer present.The solid was filtered off and the filtrate acidified with 6Nhydrochloric acid. The resulting precipitate was collected by vacuumfiltration, washed with water, and dried under vacuum to give 9.8 g (45%yield) of 1-methyl-6-nitrophenylacetic acid as an off-white solid. Thesold was hydrogenated in methanol over 10% palladium on carbon to give9.04 g of the title compound as a white solid.

[0363] (b) Preparation of 5-Nitro-2-oxindole. The 2-oxindole (6.5 g) wasdissolved in 25 mL of concentrated sulfuric acid and the mixturemaintained at −10-15° C. while 2.1 mL of fuming nitric acid was addeddropwise. After the addition of the nitric acid the reaction mixture wasstirred at 0° C. for 0.5 hr and poured into ice water. The precipitatewas collected by filtration, washed with water and crystallized from 50%of the acetic acid. The final crystal was then filtered, washed withwater and dried under vacuum to give 6.3 g (70%) of 5-nitro-2-oxindole.

[0364] (c) Preparation of 5-Amino-2-oxindole. The 5-nitro-2-oxindole(6.3 g) was hydrogenated in methanol over 10% palladium on carbon togive 3.0 g (60% yield) of the title compound as a white solid.

[0365] (d) Preparation of 5-Fluoro-2-oxindole. 5-Fluoroisatin (8.2 g)was dissolved in 50 mL of hydrazine hydrate and refluxed for 1 hr. Thereaction mixtures were then poured in ice water. The precipitate wasthen filtered, washed with water and dried under vacuum oven to give 6.0g of 5-fluoro-2-oxindole (79% yield).

[0366] (e) Preparation of 5-Bromo-2-oxindole. 2-Oxindole (1.3 g) in 20mL of acetonitrile was cooled to −10° C. and 2.0 g of N-bromosuccinimidewas slowly added with stirring. The reaction was stirred for 1 hour at−10° C. and 2 hours at 0° C. The precipitate was collected, washed withwater and dried to give 1.9 g (90% yield) of the title compound.

[0367] (f) Preparation 5-Carboxy-2-oxindole

[0368] Step 1.

[0369] Synthesis of 5-Methoxycarbonyl-2-oxindole. 5-Iodo-2-oxindole (17g) was refluxed with 2 g of palladium diacetate, 18.15 g oftriethylamine, 150 mL of methanol, 15 mL of dimethylsulfoxide and 2.6 gof DPPP in an atmosphere saturated with carbon monoxide. After 24 hours,the reaction was filtered to remove the catalyst and the filtrateconcentrated. The concentrate was chromatographed on a silica gel in 30%ethyl acetate in hexane. The fractions containing product wereconcentrated and allowed to stand. The precipitated product wascollected by vacuum filtration to give 0.8 g (7%) of the title compoundas an off-white solid.

[0370] Step 2:

[0371] Synthesis of 5-Carboxy-2-oxindole. 5-Methoxycarbonyl-2-oxindole(1 g) and 1 g of sodium hydroxide in 20 mL of methanol was refluxed for3 hours. The reaction mixture was cooled and concentrated to dryness.The residue was dissolved in water and extracted twice with ethylacetate. The aqueous layer was acidified with 6 N hydrochloric acid andthe precipitated solid collected, washed with water, and dried to give0.7 g (78%) of the title compound as an off-white solid.

[0372] (g) Preparation of 5-Carboxyethyl-2-oxindole

[0373] Step 1:

[0374] Synthesis of 5-Chloroacetyl-2-oxindole. Aluminum chloride (30.8g) and 2-oxindole (5.0 g) were added to 200 ml of carbon disulfide atroom temperature and the mixture stirred. Chloroacetyl chloride (3.8 mL)was added and the stirring continued for 1 hour. The mixture was heatedto reflux for 3 hours, cooled and the solvent decanted. The residue wasstirred in ice water until it became a solid suspension. The solid wascollected by vacuum filtration, washed in water, and dried to give 7.0 g(90% yield) of the title compound.

[0375] Step 2:

[0376] Synthesis of 5-Chloroethyl-2-oxindole. 5-Chloroacetyl-2-oxindole(7.0 g) was added to 25 mL of trifluoroacetic acid and the mixturecooled in an ice bath with stirring. Triethylsilane (12.3 mL) was addeddropwise over 2 minutes. The reaction was then stirred at roomtemperature for 4 hours and poured into ice water. Hexane was added, themixture stirred vigorously, and the solid collected by vacuum siltationand washed with hexane to give 5.9 g (91% yield) of the product as awhite solid.

[0377] Step 3:

[0378] Synthesis of 5-Cyanoethyl-2-oxindole. Potassium cyanide (2.02 g)was added to 15 mL of dimethylsulfoxide and heated to 90° C.5-Chloroethyl-2-oxindole (3.0 g) dissolved in 5 mL of dimethylsulfoxidewas added slowly with stirring, and the reaction heated to 150° C. for 2hours. The mixture was cooled, poured into ice water and the precipitatecollected by vacuum filtration, washed with water, and dried to givecrude product. The crude material was chromatographed on silica gel in5% methanol in chloroform to give 1.2 g (42% yield) of the titlecompound.

[0379] Step 4:

[0380] Synthesis of 5-Carboxyethyl-2-oxindole. 5-Cyanoethyl-2-oxindole(4.02 g) in 10 mL of water containing 25 mL of concentrated hydrochloricacid was refluxed for 4 hours. The mixture was cooled, water added andthe resulting solid collected by vacuum filtration, washed with waterand dried to give 1.9 g (44% yield) of the title compound as a yellowsolid.

[0381] (h) Preparation of 3,5-Dimethylpyrrol-2-carboxaldehyde

[0382] 5-Cyanoethly-2-oxindole (4.02 g) in 10 mL of water containing 25mL of concentrated hydrochloric acid was refluxed for 4 hours. Themixture was cooled, water added and the resulting solid collected byvacuum filtration, washed with water and dried to give 1.9 g (44% yield)of the title compound as a yellow solid.

[0383] (i) Preparation of 3,5-Dimethylpyrrol-2-carboaldehyde

[0384] To a solution dimethylformamide (80.4 g) and 1 L ofdichloroethane at 0° C. was added phosphorous oxychoride (153.3 g) overa few minutes and the reaction stirred for 1-2 hr at 0° C.2,4-Dimethylpyrrole (114.6 g) was added dropwise to the above solutionat temperature below 5° C. After the addition was complete the reactionwas heated and the aqueous layer isolated and saved. The organic layerwas extracted again with 300 mL of water and the two aqueous layerscombined. The aqueous phase was extracted with 200 mL of dichloroethaneand the organic layer discarded. The aqueous phase was cooled to 10° C.and adjusted to pH 10 with 10% sodium hydroxide. The mixture was stirredat 10° C. for 2 hr. The yellow solid was collected by vacuum filtrationand washed thoroughly with water. The solid was dried at roomtemperature under vacuum to give 110.8 g (90% yield of2,4-dimethyl-5-formylpyrrole.

[0385] (j) Preparation of 3,5-Diethylpyrrol-2-carboxaldehyde:

[0386] The solution of 25.0 g of 3,5-heptanedione and 42.3 g of diethylaminomalonate hydrochloride in 200 mL of acetic acid was heated to95-10° C. for 1.25 hr. Sodium acetate was added and the reaction mixturewas stirred for 5.35 hr and cooled down for 4 hr. The salt was filteredand washed with acetic acid. The acetic acid solution was <thenconcentrated and the residue poured into 800 mL of water. The yellowsolid was filtered and dried in a vacuum oven overnight to give 36.0 gof ethyl 3,5-diethlypyrrol-2-carboxalate as the orange liquid (92%yield).

[0387] Decarboxylation of ethyl 3,5-diethylpyrro-2-carboxalate uponhydrolysis gave 2,4-diethylpyrrole. The title compound was thensynthesized via Vilsmeier formulation of 2,4-diethlpyrrole with the samecondition used for the preparation of3,5-dimethylpyrrol-5-carboxaldehyde.

[0388] (k) Preparation of 3,5-Diisopropylpyrrol-2-carboxaldehyde

[0389] The procedure was the same as the one for the preparation of3,5-diethylpyrrol-2-carboxaldehyde except starting with2,6-dimethyl-3,5-heptanedione.

Example 2

[0390] FLK Inhibition by Indolinone Compounds of the Invention

[0391] An enzyme linked immunosorbent assay (ELISA) was conducted tomeasure the catalytic activity of the FLK-1 receptor and morespecifically, the inhibition or activation of indolinone compounds onthe catalytic activity of the FLK-1 receptor. Specifically, thefollowing assay was conducted to measure catalytic activity of the FLK-1receptor in FLK-1/NIH3T3 cells.

[0392] The materials and protocol for the FLK-1 ELISA assay are asdescribed in International Patent Publication No. WO 96/40116, publishedDec. 19, 1996 by Tang et al.

[0393] Selected compounds were tested in the FLK-1 ELISA assay. IC50measurements are reported in the tables. Derivatives of3-[(indole-3-yl)methylene]-2-indolinone compounds with a methylsubstituent at the 1′ position proved to be the most potent inhibitorsof the group of compounds tested in the assay.

Example 3

[0394] In Vitro RTK Assays

[0395] The following in vitro assays may be used to determine the levelof activity and effect of the different compounds of the presentinvention on one or more of the RTKs. Similar assays can be designedalong the same lines for any tyrosine kinase using techniques well knownin the art.

[0396] (a) Enzyme Linked Immunosorbent Assay (ELISA)

[0397] Enzyme linked immunosorbent assays (ELISA) may be used to detectand measure the presence of tyrosine kinase activity. The ELISA may beconducted according to known protocols which are described in, forexample, Voller, et al., 1980, “Enzyme-Linked Immunosorbent Assay,” In:Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp359-371 Am. Soc. Of Microbiology, Wash., D.C.

[0398] The disclosed protocol may be adapted for determining activitywith respect to a specific RTK. For example, the preferred protocols forconducting the ELISA experiments for specific RTKs is provided below.Adaptation of these protocols for determining a compound's activity forother members of the RTK family, as well as other receptor andnon-receptor tyrosine kinases, are within the scope of those in the art.

[0399] (i) FLK-1 ELISA

[0400] An ELISA assay was conducted to measure the kinase activity ofthe FLK-1 receptor and more specifically, the inhibition or activationof protein tyrosine kinase activity on the FLK-1 receptor. Specifically,the following assay was conducted to measure kinase activity of theFLK-1 receptor in FLK-1/NIH3T3 cells.

[0401] Materials And Methods

[0402] Materials.

[0403] The following reagents and supplies were used:

[0404] a. Corning 96-well ELISA plates (Corning Catalog No. 25805-96);

[0405] b. Cappel goat anti-rabbit IgG (catalog no. 55641);

[0406] c. PBS (Gibco Catalog No. 450-1300EB);

[0407] d. TBSW Buffer (50 mM Tris (pH 7.2), 150 mM NaCl and 0.1%Tween-20);

[0408] e. Ethanolamine stock (10% ethanolamine (pH 7.0), stored at 4°C.);

[0409] f. HNTG buffer (20 mM HEPES buffer (pH 7.5), 150 mM NaCl, 0.2%Triton X-100, and 10% glycerol);

[0410] g. EDTA (0.5 M (pH 7.0) as a 100× stock);

[0411] h. Sodium ortho vanadate (0.5 M as a 100× stock);

[0412] i. Sodium pyro phosphate (0.2M as a 100× stock);

[0413] j. NUNC 96 well V bottom polypropylene plates (Applied ScientificCatalog No. AS-72092);

[0414] k. NIH3T3 C7#3 Cells (FLK-1 expressing cells);

[0415] l. DMEM with 1× high glucose L Glutamine (catalog No. 11965-050);

[0416] m. FBS, Gibco (catalog no. 16000-028);

[0417] n. L-glutamine, Gibco (catalog no. 25030-016);

[0418] o. VEGF, PeproTech, Inc. (catalog no. 100-20)(kept as 1 μg/100 μlstock in Milli-Q dH₂O and stored at −20° C.;

[0419] p. Affinity purified anti-FLK-1 antiserum which can be obtainedor purified as follows:

[0420] 1. Prepare a Tresyl-Activated Agarose/Flk-1-D column byincubating 10 ml of Tresyl-Activated Agarose with 20 mg of purifiedGST-Flk-1-D fusion protein in 100 mM sodium bicarbonate (pH 9.6) bufferovernight at 40° C.

[0421] 2. Wash the column once with PBS.

[0422] 3. Block the excess sites on the column with 2 M glycine for 2hours at 40° C.

[0423] 4. Wash the column with PBS.

[0424] 5. Incubate the column with Rabbit anti-Flk-1D production bleedfor 2 hours at 40° C.

[0425] 6. Wash the column with PBS.

[0426] 7. Elute antiserum with 100 mM Citric Acid, pH3.0 and neutralizethe eluate immediately with 2 M Tris, pH 9.0.

[0427] 8. Dialyize the eluate against PBS overnight at 40° C. with 3changes of buffer (sample to buffer ratio is 1:100).

[0428] 9. Adjust the dialyized antiserum to 5% glycerol and store at−80° C. in small aliquotes.

[0429] q. UB40 monoclonal antibody specific for phosphotyrosine, (see,Fendley, et al., 1990, Cancer Research 50:1550-1558);

[0430] r. EIA grade Goat anti-mouse IGG-POD (BioRad catalog no.172-1011);

[0431] s. 2,2-azino-bis(3-ethylbenz-thiazoline-6-sulfonic acid (ABTS)solution (100 mM citric acid (anhydrous), 250 mM Na₂HPO₄ (pH 4.0), 0.5mg/ml ABTS (Sigma catalog no. A-1888)), solution should be stored indark at 4° C. until ready for use;

[0432] t. H₂O₂ (30% solution) (Fisher catalog no. H325);

[0433] u. ABTS/H₂O₂ (15 ml ABTS solution, 2 μl H₂O₂) prepared 5 minutesbefore use and left at room temperature;

[0434] v. 0.2 M HCl stock in H₂O;

[0435] w. dimethylsulfoxide (100%) (Sigma Catalog No. D-8418); and

[0436] x. Trypsin-EDTA (Gibco BRL Catalog No. 25200-049).

[0437] Protocol

[0438] The following protocol was used for conducting the assay:

[0439] 1. Coat Corning 96-well elisa plates with 1.0 μg per well CappelAnti-rabbit IgG antibody in 0.1M Na₂CO₃ pH 9.6. Bring final volume to150 μl per well. Coat plates overnight at 4° C. Plates can be kept up totwo weeks when stored at 4° C.

[0440] 2. Grow cells in Growth media (DMEM, supplemental with 2.0 mML-Glutamine, 10% FBS) in suitable culture dishes until confluent at 37°C., 5% CO₂.

[0441] 3. Harvest cells by trypsinization and seed in Corning 25850polystyrene 96-well roundbottom cell plates, 25.000 cells/well in 200 μlof growth media.

[0442] 4. Grow cells at least one day at 37° C., 5% CO₂.

[0443] 5. Wash cells with D-PBS 1×.

[0444] 6. Add 200 μl/well of starvation media (DMEM, 2.0 mM 1-Glutamine,0.1% FBS). Incubate overnight at 37° C., 5% CO₂.

[0445] 7. Dilute Compounds/Extracts 1:20 in polypropylene 96 well platesusing starvation media. Dilute dimethylsulfoxide 1:20 for use in controlwells.

[0446] 8. Remove starvation media from 96 well cell culture plates andadd 162 μl of fresh starvation media to each well.

[0447] 9. Add 18 μl of 1:20 diluted Compound/Extract dilution (from step7) to each well plus the 1:20 dimethylsulfoxide dilution to the controlwells (+/−VEGF), for a final dilution of 1:200 after cell stimulation.Final dimethylsulfoxide is 0.5%. Incubate the plate at 37° C., 5% CO₂for two hours.

[0448] 10. Remove unbound antibody from ELISA plates by inverting plateto remove liquid. Wash 3 times with TBSW +0.5% ethanolamine, pH 7.0. Patthe plate on a paper towel to remove excess liquid and bubbles.

[0449] 11. Block plates with TBSW +0.5% Ethanolamine, pH 7.0, 150 μl perwell. Incubate plate thirty minutes while shaking on a microtiter plateshaker.

[0450] 12. Wash plate 3 times as described in step 10.

[0451] 13. Add 0.5 μg/well affinity purified anti-FLU-1 polyclonalrabbit antiserum. Bring final volume to 150 μl/well with TBSW +0.5%ethanolamine pH 7.0. Incubate plate for thirty minutes while shaking.

[0452] 14. Add 180 μl starvation medium to the cells and stimulate cellswith 20 μl/well 10.0 mM sodium ortho vanadate and 500 ng/ml VEGF(resulting in a final concentration of 1.0 mM sodium ortho vanadate and50 ng/ml VEGF per well) for eight minutes at 37° C., 5% CO₂. Negativecontrol wells receive only starvation medium.

[0453] 15. After eight minutes, media should be removed from the cellsand washed one time with 200 μl/well PBS.

[0454] 16. Lyse cells in 150 μl/well HNTG while shaking at roomtemperature for five minutes. HNTG formulation includes sodium orthovanadate, sodium pyro phosphate and EDTA.

[0455] 17. Wash ELISA plate three times as described in step 10.

[0456] 18. Transfer cell lysates from the cell plate to elisa plate andincubate while shaking for two hours. To transfer cell lysate pipette upand down while scrapping the wells.

[0457] 19. Wash plate three times as described in step 10.

[0458] 20. Incubate ELISA plate with 0.02 μg/well UB40 in TBSW +05%ethanolamine. Bring final volume to 150 μl/ well. Incubate while shakingfor 30 minutes.

[0459] 21. Wash plate three times as described in step 10.

[0460] 22. Incubate ELISA plate with 1:10,000 diluted EIA grade goatanti-mouse IgG conjugated horseradish peroxidase in TBSW +0.5%ethanolamine, pH 7.0. Bring final volume to 150 μl/well. Incubate whileshaking for thirty minutes.

[0461] 23. Wash plate as described in step 10.

[0462] 24. Add 100 μl of ABTS/H₂O₂ solution to well. Incubate tenminutes while shaking.

[0463] 25. Add 100 μl of 0.2 M HCl for 0.1 M HCl final to stop the colordevelopment reaction. Shake 1 minute at room temperature. Remove bubbleswith slow stream of air and read the ELISA plate in an ELISA platereader at 410 nm.

[0464] (ii) HER-2 ELISA

[0465] HER-2 ELISA assays are described in International PatentPublication No. WO 96/40116, published Dec. 19, 1996 by Tang et al.

[0466] (iii) PDGF-R ELISA

[0467] A PDGF-R ELISA is described in International Patent PublicationNo. WO 96/40116, published Dec. 19, 1996 by Tang et al.

[0468] (iv) IGF-I ELISA

[0469] The IGF-I ELISA protocol described in International PatentPublication No. WO 96/40116, published Dec. 19, 1996 by Tang et al. maybe used to measure phosphotyrosine level on IGF-I receptor, whichindicates IGF-I receptor tyrosine kinase activity.

[0470] (v) EGF Receptor ELISA

[0471] EGF Receptor kinase activity (EGFR-NIH3T3 assay) in whole cellswas measured as described in International Patent Publication No. WO96/40116, published Dec. 19, 1996 by Tang et al.

[0472] (vi) Cellular Insulin Receptor ELISA

[0473] The protocol described in International Patent Publication No. WO96/40116, published Dec. 19, 1996 by Tang et al. was used to determinewhether the compounds of the present invention possessed insulinreceptor tyrosine kinase activity.

[0474] (vii) EGFR ELISA ASSAY

[0475] Purpose

[0476] To provide a consistent method for measuring the in vitro kinaseactivity of the EGFR in an Enzyme-linked immunosorbent assay (Elisa).

[0477] Scope

[0478] The following protocol describes the procedures used to analyzeprotein tyrosine kinase activity on the EGFR in an Elisa. The procedurealso describes the protocol for the initial screening of drugs forinhibition or activation of protein tyrosine kinase activity.

[0479] Reagents and Supplies

[0480] 1. Corning 96-well Elisa plates

[0481] Corning Catalog #25805-96

[0482] 2. 05-101 monoclonal anti-EGFR antibody (commercially availablefrom UB1)

[0483] −80° C., 1 ml aliquots

[0484] 3. PBS (Dulbecco's Phosphate-Buffered Saline)

[0485] Gibco Catalog #450-1300EB Formulation: 2.7 mM KCL 1.1 mM KH2PO₄0.5 mM MgCl₂ (anhydrous) 138 mM NaCl 8.1 mM Na2HPO₄

[0486] 4. TBST Buffer Formulation: 50 mM Tris pH 7.2 150 mM NaCl 0.1%Triton X-100

[0487] 5. Blocking Buffer

[0488] Formulation: 5% Carnation Instant Milk in PBS

[0489] 6. A431 cell lysate

[0490] A431 cells are available from a variety of commercial sources andmay be used lysed using conventional methods known to those skilled inthe art or as described for lysis of the 3T3 cells in the EGF cellularassay described herein. −80° C., 1 ml aliquots

[0491] 7. TBS Buffer Formulation: 50 mM Tris pH 7.2 150 mM NaCl

[0492] 8. TBS +10% DMSO

[0493] Formulation: 10% DMSO in TBS Buffer

[0494] (DMSO from Sigma, Catalog # D-2650)

[0495] 9. ATP/MnCl₂ phosphorylation mix Formulation: 0.03 mM ATP

[0496] (Adenosine-5′-triphosphate, Sigma Catalog #A-5394)

[0497] 50 mM MnCl₂

[0498] Make fresh in autoclaved Milli-Q H2O immediately before use

[0499] Keep on ice until use

[0500] 10. NUNC 96-well V bottom polypropylene plates

[0501] Applied Scientific Catalog # AS—72092

[0502] 11. EDTA Formulation: 200 mM EDTA pH 8.0

[0503] 12. Rabbit polyclonal anti-phosphotyrosine serum or UB40monoclonal antibody specific for phosphotyrosine or UBI's mab 4610,Upstate Biotechnology, Lake Placid, N.Y., Catalog # 05-321

[0504] −80° C., 1 ml aliquots

[0505] Thaw 1 ml vial and aliquot in smaller volumes to store at −80° C.

[0506] Antiserum is stable for weeks when thawed and stored at 4° C.

[0507] 13. Goat anti-rabbit IgG peroxidase conjugate

[0508] Biosource Catalog # ALI0404

[0509] 14. ABTS Solution Formulation: 100 mM Citric Acid (anhydrous) 250mM Na₂HPO4 pH 4.0 0.5 mg/ml ABTS

[0510] (2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)

[0511] (Sigma Catalog # A-1888)

[0512] Keep solution in dark at 4° C. until ready to use

[0513] 15. Hydrogen peroxide 30% solution

[0514] Fisher Catalog # H325

[0515] Store in the dark at 4° C. until ready to use

[0516] 16. ABTS/H₂O₂ Formulation: 15 mls ABTS solution 2 ul H₂O₂

[0517] Prepare 5 minutes before use and room temperature

[0518] 17. 0.2 M HCL stock in H₂O

[0519] Procedure

[0520] 1. Coat Corning 96-well elisa plates with 0.5 ug per well 05-101antibody.

[0521] Bring final volume to 100 ul per well with PBS.

[0522] Coat plates overnight at 40° C.

[0523] 2. Remove unbound 05-101 from wells by inverting plate to removeliquid.

[0524] Wash 1× with distilled H2O by filling wells

[0525] Pat the plate on a paper towel to remove excess liquid.

[0526] 3. Block plates with 5% milk in PBS.

[0527] 150 ul per well.

[0528] Incubate plate 30 minutes while shaking on a microtiter plateshaker.

[0529] 4. Wash plate 3× with dionized water, then once with TBST

[0530] 5. Add 7 ug A431 cell lysate per well (EGFR source).

[0531] Add PBS to final volume of 100 ul per well

[0532] Incubate 30 minutes while shaking.

[0533] 6. Wash as described in step 4.

[0534]7. At this point, drugs or extracts are added to the wells.

[0535] Dilute drugs/extracts 1:100 (unless specified otherwise) in TBS+10% DMSO in 96-well polypropylene plates.

[0536] Add 120 ul TBS to ELISA plate containing captured EGFR.

[0537] Add 13.5 ul diluted drugs/extracts to ELISA plate.

[0538] To control wells (wells which do not receive any drug) add 135 ulTBS

[0539] +1% DMSO.

[0540] Incubate plate 30 minutes while shaking.

[0541] 8. Add 15 ul of 0.03 mM ATP +50 mM MnCl₂ phosphorylation mixdirectly to all wells except negative control well which does notreceive ATP/MnCl₂ (see diagram).

[0542] (150 ul final volume in well with 3 uM ATP/5 mM MnCl2 finalconcentration in well.)

[0543] Incubate 5 minutes while shaking vigorously.

[0544] *NOTE: It is critical that ATP/MnCl2

[0545] phosphorylates the receptor for 5 minutes only.

[0546] It is best to add the ATP/MnCl₂ with an 12 channel pipettor 1 rowat a time leaving 20 seconds between each row so that the reaction maybe stopped with EDTA exactly 5 minutes later (this depends on the numberof plates being phosphorylated in one batch). Shake between eachaddition.

[0547] 9. After 5 minutes, to stop reaction, add 16.5 ul of 200 mM EDTApH 8.0 for 20 mM final in well, shaking continuously between eachaddition. This is done using the same timing method as above. After lastrow has received EDTA, shake plate an additional minute.

[0548] 10. Wash 4× with deionized water, twice with TBST.

[0549] 11. Add rabbit polyclonal anti-phosphotyrosine serum.

[0550] Dilute 1:3000 in TBST.

[0551] Add 100 ul per well.

[0552] Incubate 30-45 minutes while shaking.

[0553] 12. Wash as described above in step 4.

[0554] 13. Add BioSource anti-rabbit peroxidase conjugate antibody.

[0555] Dilute 1:2000 in TBST.

[0556] Add 100 ul per well.

[0557] Incubate 30 minutes while shaking.

[0558] 14. Wash as described in step 4.

[0559] 15. Add 100 ul of ABTS/H₂O₂ solution to well.

[0560] Incubate 5 to 10 minutes while shaking.

[0561] Remove bubbles

[0562] 16. If necessary stop reaction with the addition of 100 ul of0.2M HCl per well

[0563] 17. Read assay on Dynatech MR7000 elisa reader.

[0564] Test Filter: 410 nM

[0565] Reference Filter: 630 nM

[0566] (b) Cell Growth Assays

[0567] The cell growth assays described in International PatentPublication No. WO 96/40116, published Dec. 19, 1996 by Tang et al. maybe conducted to measure the effect of the claimed compounds upon cellgrowth as a result of the compound's interaction with one or more RTKs.

[0568] (vi) Assay Measuring Phosphorylating Function of Raf

[0569] The following assay reports the amount of RAF-catalyzedphosphorylation of its target protein MEK as well as MEK's target MAPK.The RAF gene sequence is described in Bonner et al., 1985, Molec. Cell.Biol. 5:1400-1407, and is readily accessible in multiple gene sequencedata banks. Construction of the nucleic acid vector and cell linesutilized for this portion of the invention are fully described inMorrison et al., 1988, Proc. Natl. Acad. Sci. USA 85: 8855-8859.

[0570] Materials and Reagents

[0571] 1. Sf9 (Spodoptera frugiperda) cells; GIBCO-BRL, Gaithersburg,Md.

[0572] 2. RIPA buffer: 20 mM Tris/HCl pH 7.4, 137 mM NaCl, 10% glycerol,1 mM PMSF, 5 mg/L Aprotenin, 0.5% Triton X-100;

[0573] 3. Thioredoxin-MEK fusion protein (T-MEK): T-MEK expression andpurification by affinity chromatography were performed according to themanufacturer's procedures. Catalog# K 350-01 and R 350-40, InvitrogenCorp., San Diego, Calif.

[0574] 4. His-MAPK (ERK 2); His-tagged MAPK was expressed in XL1 Bluecells transformed with pUC18 vector encoding His-MAPK. His-MAPK waspurified by Ni-affinity chromatography. Cat# 27-4949-01, Pharmacia,Alameda, Calif.

[0575] 5. Sheep anti mouse IgG: Jackson laboratories, West Grove, Pa.Catalog, # 515-006-008, Lot# 28563

[0576] 6. RAF-1 protein kinase specific antibody: URP2653 from UBI.

[0577] 7. Coating buffer: PBS; phosphate buffered saline, GIBCO-BRL,Gaithersburg, Md.

[0578] 8. Wash buffer: TBST −50 mM Tris/HCL pH 7.2, 150 mM NaCl, 0.1%Triton X-100

[0579] 9. Block buffer: TBST, 0.1% ethanolamine pH 7.4

[0580] 10. DMSO, Sigma, St. Louis, Mo.

[0581] 11. Kinase buffer (KB): 20 mM Hepes/HCl pH 7.2, 150 mM NaCl, 0.1%Triton X-100, 1 mM PMSF, 5 mg/L Aprotenin, 75 μM sodium ortho vanadate,0.5 mM DTT and 10 mM MgCl₂.

[0582] 12. ATP mix: 100 mM MgCl₂, 300 μM ATP, 10 μCi γ-³³P ATP(Dupont-NEN) /mL.

[0583] 13. Stop solution: 1% phosphoric acid; Fisher, Pittsburgh, Pa.

[0584] 14. Wallac Cellulose Phosphate Filter mats; Wallac, Turku,Finland.

[0585] 15. Filter wash solution: 1% phosphoric acid, Fisher, Pittsburgh,Pa.

[0586] 16. Tomtec plate harvester, Wallac, Turku, Finland.

[0587] 17. Wallac beta plate reader # 1205, Wallac, Turku, Finland.

[0588] 18. NUNC 96-well V bottom polypropylene plates for compoundsApplied Scientific Catalog # AS-72092.

[0589] Procedure

[0590] All of the following steps are conducted at room temperatureunless specifically indicated.

[0591] 1. ELISA plate coating: ELISA wells are coated with 100 μL ofSheep anti mouse affinity purified antiserum (1 μg/100 μL coatingbuffer) over night at 4° C. ELISA plates can be used for two weeks whenstored at 4° C.

[0592] 2. Invert the plate and remove liquid. Add 100 μL of blockingsolution and incubate for 30 min.

[0593] 3. Remove blocking solution and wash four times with wash buffer.Pat the plate on a paper towel to remove excess liquid.

[0594] 4. Add 1 μg of purified Sumo 22 to each well and incubate for 1hour. Wash as described in step 3.

[0595] 5. Thaw lysates from RAS/RAF infected Sf9 cells and dilute withTBST to 10 μg/100 μL. Add 10 μg of diluted lysate to the wells andincubate for 1 hour. Shake the plate during incubation. Negativecontrols receive no lysate. Lysates from RAS/RAF infected Sf9 insectcells are prepared after cells are infected with recombinantbaculoviruses at a MOI of 5 for each virus, and harvested 48 hourslater. The cells are washed once with PBS and lysed in RIPA buffer.Insoluble material is removed by centrifugation (5 min at 10 000× g).Aliquots of lysates are frozen in dry ice/ethanol and stored at −80° C.until use.

[0596] 6. Remove non-bound material and wash as outlined above (step 3).

[0597] 7. Add 2 μg of T-MEK and 2 μg of His-MAPK per well and adjust thevolume to 40 μL with kinase buffer.

[0598] 8. Predilute compounds (stock solution 10 mg/mL DMSO) or extracts20 fold in TBST plus 1% DMSO. Add 5 μL of the predilutedcompounds/extracts to the wells described in step 6. Incubate for 20min. Controls receive no drug.

[0599] 9. Start the kinase reaction by addition of 5 μL ATP mix; Shakethe plates on an ELISA plate shaker during incubation.

[0600] 10. Stop the kinase reaction after 60 min by addition of 30 μLstop solution to each well.

[0601] 11. Place the phosphocellulose mat and the ELISA plate in theTomtec plate harvester. Harvest and wash the filter with the filter washsolution according to the manufacturers recommendation. Dry the filtermats. Seal the filter mats and place them in the holder. Insert theholder into radioactive detection apparatus and quantitate theradioactive phosphorous on the filter mats.

[0602] Alternatively, 40 μL aliquots from individual wells of the assayplate can be transferred to the corresponding positions on thephosphocellulose filter mat. After air-drying the filters, put thefilters in a tray. Gently rock the tray, changing the wash solution at15 min intervals for 1 hour. Air-dry the filter mats. Seal the filtermats and place them in a holder suitable for measuring the radioactivephosphorous in the samples. Insert the holder into a detection deviceand quantitate the radioactive phosphorous on the filter mats.

[0603] (c) Toxicity and Animal Models

[0604] Measurement Of Cell Toxicity and In Vivo Animal Models aredescribed in International Patent Publication No. WO 96/40116, publishedDec. 19, 1996 by Tang et al.

[0605] (d) MET Biochemical Kinase Assay

[0606] A met biochemical kinase assay may be performed for met generallyas described above for other kinases by substituting that or the otherkinases. In particular, ELISA plates are coated with goat anti-rabbit Fcantibodies, which are used to capture commercially available (from SantaCruz Biotechnology) rabbit polyclonal antibodies to the cytoplasmicdomain of human MET. Lysates are made from 293T cells that have beentransiently transfected with a chimeric receptor composed of theextracellular domain of the EGFr and the transmembrane and cytoplasmicdomain of the MET receptor, or from NCI-H441 cells (a human lungadenocarcinoma cell line) which express high endogenous levels of MET.The chimeric receptors, or MET, from these lysates are captured on theantibody coated plates. After washing away extraneous proteins, testcompounds are added and an in vitro kinase assay is performed byaddition of an appropriate kinase buffer (containing ATP, divalent metalions, etc.). Incorporation of phosphate into the captured receptors isdetected with an anti-phosphotyrosine antibody conjugate with horseradish peroxidase using TMB as a substrate for colorimetric detection.

[0607] The present invention is not to be limited in scope by theexemplified embodiments which are intended as illustrations of singleaspects of the invention. Indeed, various modifications of the inventionin addition to those described herein will become apparent to thoseskilled in the art from the foregoing description and accompanyingdrawings. Such modifications are intended to fall within the scope ofthe appended claims.

[0608] All references cited herein are hereby incorporated by referencein their entirety.

[0609] Other embodiments are within the following claims. TABLE 1

[0610] TABLE 2 FLK Kinase IC50 (μM) STRUCTURES 0.7

7.7

2.5

14

13

[0611] TABLE 3 NUMBER ID STRUCTURE 1 ind/ald-001

2 ind/ald-002

3 ind/ald-003

4 ind/ald-004

5 ind/ald-005

6 ind/ald-006

7 ind/ald-007

8 ind/ald-008

9 ind/ald-009

10 ind/ald-010

11 ind/ald-011

12 ind/ald-012

13 ind/ald-013

14 ind/ald-014

15 ind/ald-015

16 ind/ald-016

17 ind/ald-017

18 ind/ald-018

19 ind/ald-019

20 ind/ald-020

21 ind/ald-021

22 ind/ald-022

23 ind/ald-023

24 ind/ald-024

25 ind/ald-025

[0612] TABLE 4 NUMBER CORP ID STRUCTURE 1 oxindole-001

2 oxindole-002

3 oxindole-003

4 oxindole-004

5 oxindole-005

6 oxindole-006

7 oxindole-007

8 oxindole-008

9 oxindole-009

10 oxindole-010

11 oxindole-011

12 oxindole-012

13 oxindole-013

14 oxindole-014

15 oxindole-015

16 oxindole-016

17 oxindole-028

18 oxindole-036

19 oxindole-037

20 oxindole-038

21 oxindole-039

22 oxindole-040

23 oxindole-041

24 oxindole-045

25 oxindole-048

26 oxindole-050

27 oxindole-054

28 oxindole-056

29 oxindole-057

30 oxindole-058

31 oxindole-059

32 oxindole-060

33 oxindole-061

34 oxindole-062

[0613] TABLE 5 Structure

Formula C₁₇H₁₅BrN₂O M.W. 343.2230

Formula C₁₇H₁₆N₂O M.W. 264.3260

Formula C₁₈H₁₈N₂O M.W. 278.3530

[0614] TABLE 6 FLK Kinase IC50 (μM) STRUCTURES 1.2

1.4

5

[0615] TABLE 7 Structure 0128

Activity 1C50 = 1.7 μm 1C50 = 6.8 μm FLK Kinase PDGF Kinase Structure0129

Activity 1C50 = 19.6 μm 1C50 = 0.8 μm FLK Kinase PDGF Kinase

[0616] TABLE 8 SU # Structure Activity

EC₂₀₀ = 2.8 μm

EC₂₀₀ = 2.8 μm

EC₂₀₀ = 10 μm

EC₂₀₀ = 32 μm

EC₂₀₀ >100 μm

EC₂₀₀ = 46 μm

[0617] TABLE 9 3-[(pyrrol-2-yl)methylidenyl]-5-sulfonyl-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-sulfonyl-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-sulfonyl-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-sulfonyl-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-sulfonyl-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-sulfonyl-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-aminosulfonyl-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-aminosulfonyl-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-aminosulfonyl-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-aminosulfonyl-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-aminosulfonyl-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-aminosulfonyl-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-methoxycarbonyl-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-methoxycarbonyl-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-methoxycarbonyl-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-methoxycarbonyl-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-melhoxycarbonyl-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-methoxycarbonyl-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-diethanolamino-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-diethanolamino-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-diethanolamino-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-diethanolamino-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-diethanolamino-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-diethanolamino-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-(2,3-dihydroxypropylamino)-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-(2,3-dihydroxypropylamino)-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol5-yl)methylidenyl]-5-(2,3-dihydroxypropylamino)-2- indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-(2,3-dihydroxypropylamino)2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-(2,3-dihydroxypropylamino)-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-(2,3-dihydroxypropylamino)-2-3-[(pyrrol-2-yl)methylidenyl]-5-ureido-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-ureido-2-indolinone3-[(2,4-dimethyl-3-ethoxycabonylpyrrol-5-yl)methylidenyl]-5-ureido2-indolinone 3-[(2-methylthien-5-yl)methylidenyl]-5-ureido-2-[indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-ureido-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-ureido-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-guanidino-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-guanidino-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-guanidino-2-indolinone3-[(2-methtlthien-5-yl)methylidenyl]-5-guanidino-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-guanidino-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-guanidino-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-glyceroylamido-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-glyeroylamido-2-indolinone3-[(24-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-glyceroylamido-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-glyceroylamido-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-glyceroylamido-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-glyceroylamido-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-[(3-piperidinyl)propanoylamino-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-[(3-piperidinyl)propanoylamino]-2-indolinone3-[(2,4-dimethyl-3-ethoxycabonylpyrrol-5-yl)methylidenyl]-5-[(3-pipeeridinyl)propanoylamino]-2-indolinone3-[(2-methylthien-5-yl)methylidenyl-5-[(3-piperidinyl)propanoylamino]-2-indolinone3-[(3-methylthien-2-yl)methylidenyl-5-[(3-piperidinyl)propanoylamino]-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-[(3-piperidinyl)propanoylamino]-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-mesylamino-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-mesylamino-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl-5-mesylamino-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-mesylamino-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-mesylamino-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl)-5-mesylamino-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-glycoloyloxy-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-glycoloyloxy-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-glycoloyloxy-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-glycoloyloxy-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-glycoloyloxy-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-glycoloyloxy-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-(2,3-dihydloxypropoxy)-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-(2,3-dihydroxypropoxy)-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-(2,3-dihydroxypropoxy)-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-(2,3-dihydroxypropoxy)-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-(2,3-dihydroxypropoxy)-2-indolinone3-[4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-(2,3-dihydroxypropoxy)-2-indolnone 3-[(pyrrol-2-yl)methylidenyl]-5-aminomethyl-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-aminomethyl-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-aminomethyl-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-aminomethyl-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-aminomethyl-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-aminomethyl-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-amidino-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-amidino-2-indolione3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-amidino-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-amidino-2-indolinone3-[(3-methylhien-2-yl)methylidenyl]-5-amidino-2-indolinone 3-[(4,56,7-tetrahydroindol-3-yl)methylidenyl]-5-amidino-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-hydroxymethyl-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl] 5-hydroxymethyl-2-indolinone3-[(2,4-dimethyl-3-ethoxycabonylpyrrol-5-yl)methylidenyl-5-hydroxymethyl-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-hydroxymethyl-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-hydroxymethyl-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-hydroxymethyl-2-indolinone3-[(pyrrol-2-yl)methylidenyl)-5-phosphonooxy-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-phosphonoxy-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-phosphonooxy-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-phosphonooxy-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-phosphonooxy-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-phosphonooxy-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-ethoxycarbonyl-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-ethoxycarbony-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-ethoxycarbonyl-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-ethoxycarbonyl-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-ethoxycarbonyl-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-ethoxycarbonyl-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-benzyloxycarbonyl-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-benzyloxycarbonyl-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl-5-benzyloxycarbonyl-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-benzyloxycarbonyl-2-indolinone5-benzyloxycarbonyl-2- indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-benzyloxycarbonyl-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-benzyloxycarbonyl-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-phenylaminocarbonyl-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-phenylaminocarbonyl-2-indolinone3-[(2,4-dimethyl-3-ethoxycarbonylpyrrol-5-yl)methylidenyl]-5-phenylaminocarbonyl-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-phenylaminocarbonyl-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-phenylaminocarbonyl-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yi)methylidenyl]-5-phenylaminocarbonyl-2-indolinone3-[(pyrrol-2-yl)methylidenyl]-5-benzylaminocarbonyl-2-indolinone3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-5-benzylaminocarbonyl-2-indolinone3-[(2-methylthien-5-yl)methylidenyl]-5-benzylaminocarbonyl-2-indolinone3-[(3-methylthien-2-yl)methylidenyl]-5-benzylaminocarbonyl-2-indolinone3-[(4,5,6,7-tetrahydroindol-3-yl)methylidenyl]-5-benzylaminocarbonyl-2-indolinone

[0618] TABLE 10 FLK Kinase IC50 (μM) STRUCTURES METHOD 1.6

A 2.6

A 1.9

B 4.7

B 5.6

B 10.8

B 12.5

A 0.97

B 1.5

B 1.1

B 3.5

A 7.3

A 5.6

B 8.1

A 17.3

A 2.9

B 5.2

B 18.5

B 8.8

B 4

B 8

B 11.5

B 13.7

B 10.4

B 10.7

B 16.4

B 19.9

B 9.7

B 20.3

B 4.6

B 5.6

B 9.9

A 12.3

B 18.4

B 5.8

B 6.2

A 17.1

B

[0619] TABLE 11 5-aminooxindole 5-bromooxindole 5-chloroxindoleoxindole-001 oxindole-002 oxindole-003 4,5-dimethyloxindole5,5-dimethoxyoxindole oxindole oxindole-004 oxindole-005 oxindole-0064-methyloxindole 5,7-dibromooxindole 7-bromo-5-chlorooxindoleoxindole-007 oxindole-008 oxindole-009 5-fluorooxindole 5-nitrooxindole5-iodooxindole oxindole-010 oxindole-011 oxindole-0125-chloro-7-methyloxindole 5-methyloxindole 5-bromo-4-methyloxindoleoxindole-013 oxindole-014 oxindole-015 7-fluorooxindole 7-chlorooxindole4-fluoroooxindole oxindole-016 oxindole-017 oxindole-0186-fluorooxindole 4-chlorooxindole 6-chlorooxindole oxindole-019oxindole-020 oxindole-021 5-bromo-7-mathyloxindole7-chloro-5-cyanooxindole 4-bromooxindole oxindole-022 oxindole-023oxindole-024 7-methoxyoxindole 4-methyl-5-carboxyoxindole4-methyl-5-carboxymethyloxindo le oxindole-025 oxindole-026 oxindole-0274-methyl-5-(3-carboxyethyloxindole 4-methyl-5-(3-carboxy-n-propyl)4-methyl-5-hydroxymethyloxindo le oxindole-028 oxindole-029 oxindole-0304-methyl-5-methoxymethyloxind 4-methyl-5-(2-hydroxyethyl)oxin4-methyl-5-(2-methoxyethyl)oxin ole dole dole oxindole-031 oxindole-032oxindole-033 4-methyl-5-(3-hydroxy-n-propyl)4-methyl-5-(3-methoxy-n-propyl) 5-aminosulfonyloxindole oxindoleoxindole oxindole-034 oxindole-035 oxindole-0365-methylaminosulfonyloxindole 5-(4-trifluoromethylanilinosulfony5-(morpholin-1-yl-sulfonyl)oxind l)oxindole ole oxindole-037oxindole-038 oxindole-039 6-trifluoromethyloxindole5-(2-chloroethyl)oxindole 5-carboxymethyloxindole oxindole-040oxindole-041 oxindole-042 6-carboxymethyloxindole4-methoxycarbonyloxindole 5-methoxycarbonyloxindole oxindole-043oxindole-044 oxindole-045 6-methoxycarbonyloxindole 4-carboxyoxindole5-carboxyoxindole oxindole-046 oxindole-047 oxindole-0486-carboxyoxindole 5-carboxyethyloxindole 5-hydroxyethyloxindoleoxindole-049 oxindole-050 oxindole-051 4-methyl-5-aminooxindole4-methyl-5-nitrooxindole 4-methyl-5-iodooxindole oxindole-052oxindole-053 oxindole-054 4-methyl-5-chlorooxindole oxindole-055

[0620] TABLE 12 2-ethoxybenzaldehyde 2-thioprienecarboxaldegyde1-methylpyrrole-2-carboxaldehyde CHO-001 CHO-002 CHO-0034-fluorobenzaldehyde indole-3-carboxaldehyde5-methylthiophene-2-carboxaldehyde CHO-004 CHO-005 CHO-0064-bromobenzaldehyde pyrrole-2-carboxaldehyde2-Hydroxy-2-methoxycenzaiden yde CHO-007 CHO-008 CHO-0093-methyl-2-thiophenecarboxaide 3,4-Dibromo-5-methyl-2-pyrrolecEthyl-2-4-Dimethyl-5-formyl-3-py hyde arboxaldehyde rrolecarboxylateCHO-010 CHO-011 CHO-012 3-Bromo-2-hydroxy-5-methoxyb1-Hydroxy-2-naphthaldehyde Ethyl-2-(ethoxycarbonyl)-4-(ethox enzaldehydeycarbonylmethyl)-5-formyl-3-pym cieoroolonate CHO-013 CHO-014 CHO-015Ethyl-5-formyl-2-methyl-3-furanc 4-Formyl-3-methoycarbonymeth2-Hydroxy-3-nitorbenzaldehyde arboxylate yl-5-me-1H-pyrrole-2-carboxylicacid methyl ester CHO-016 CHO-017 CHO-018 2,4-Dihydroxy-3-methylbenzaldeMethyl(5-formyl-4-methy-3-pyrrol 2-furaldehyde hyde epropionate CHO-019CHO-020 CHO-021 5-Nitor-2-furaldehyde 4-Ethoxy-3-methoxybenzaldeny3,4-Dihydroxybenzaldehyde de CHO-022 CHO-023 CHO-0242,4-Dimethoxybenzaldehyde 3,5-Demethyl-4-ethyl-2-pyrrolicar2,4,6-inmethoxybenzaldehyde boxaldehyde CHO-025 CHO-026 CHO-0274-Hydroxybenzaldehyde 4-(Dimethylamino)-benzaldehyde2,4-Dimethyl-3-carboxypyrrol e-5-carboxaldehyde CHO-028 CHO-029 CHO-0302-CHLORO-4-fluorobenzaldehyde 3-Nitrobenzaldehyde4-Fluro-2-(influoromethyl)benz aldehyde CHO-031 CHO-032 CHO-0332,4,6-Trifluorobenzaldehyde 4-Hydroxy-2-methoxybenzalden3,4-Dimethoxybenzaldehyde yde CHO-034 CHO-035 CHO-036 SalicylaldehydeBenzaldehyde 3,5-diethylpyrrole-2-carboxaldeh yde CHO-037 CHO-038CHO-039 5-(Methylthio)thioprene-2-carbo 2,4-Dihydroxy-8-methylbenzaldeMethyl-5-formyl-4-methyl-3-pyrr xaidehyde hyde olepropionate CHO-040CHO-041 CHO-042 3-Ethoxy-4-bydroxybenzaldehyde2-Hydroxy-5-methoxybenzalden 2-imidazolecarboxaldehyde yde CHO-042CHO-043 CHO-044 1-Methyl-2-formylbenzimidazole4-Chloro-1-methylpyrazole-3-car 2,3-dimethyl-5-formylthipheneboxaldehyde CHO-045 CHO-046 CHO-047 2-Formyl-4,5,6,7-tetrahydroinool3-Chloromethyl-5-nitrosilicylaid 1-(3,5-Dichlorophenyl)pyrrole-2- eenyde carboxaldehyde CHO-048 CHO-049 CHO-0505-Chlorothiophene-2-carboxalde 3,5-dimethyl-5-formylpyrrole3-t-Butyl-4-hydroxybenzaldehyd hyde e CHO-051 CHO-052 CHO-0533-t-Butyl-5-bromo-4-hydroxyben 3,5-Di-tert-butyl-4-hydroxybenza3-t-Butyl-4-hydroxy-5-nitorcenza zaldehyde ldehyde hemhydrate ldehydeCHO-054 CHO-055 CHO-056 2,4,3-Trihydroxybenzaldehyde2-formyl-5-nitrothlophene 4-Carboxybenzaldehyde CHO-057 CHO-058 CHO-0592,4-difluorobenzaldehyde 3,5-Dimethyl-4-hydroxybenzalde3-Chloro-4-hydroxy-5-t-butylben hyde zaldehyde CHO-060 CHO-061 CHO-0624-Ethoxy-3-methoxybenzaldehy 2-Nitrothiophene-4-carboxalden4-(Dibutylamino)benzaldehyde de yde CHO-063 CHO-064 CHO-0654(Trifluoromethyl)benzaldehyde 4,6Dimethoxy-salicylehyde2,3,4-Trihydroxybenzaldehyde CHO-066 CHO-067 CHO-0682-Hydroxy-3-methoxybenzalden 5-Bromo-3,4-dihydroxybenzalde3,4-Diacetoxybenzaldehyde CHO-069 CHO-070 CHO-0714-Hydroxy-3-methylbenzaldehyd 2-Bromobenzaldehyde2,4-Dihydroxybenzaldehyde CHO-072 CHO-073 CHO-0742-hydroxy-3-methoxybenzalden 3-Bromobenzaldehyde3,5-Di-tert-butyl-2-hydroxybenza yde ldehyde CHO-075 CHO-076 CHO-0774-Carboxybenzaldehyde 4-Dimethylamino-t-naphthalden4-Hydroxy-3-nitrobenzaldehyde yde CHO-078 CHO-079 CHO-0802-Hydroxy-4-methoxybenzalden 3-Hydroxy-4-nitorbenzaldehyde4-Bromobenzaldehyde yde CHO-081 CHO-082 CHO-0832,3,5,7-Tetrahydro-8-hydroxy-1 3,5-Diisoprophl-4-hydroxybenzalBenzo(b)furan-2-carboxaldehyde H,5H-benzo(ij)quinolizine.9 dehydecarboxaldehyde CHO-084 CHO-085 CHO-086 3,5-olido-4-methyl-2-pyrrolecar1-(4-chlorophenyl)pyrrole-2-caro 5-Ethyl-2-fluraldehyde boxasldehydeoxaldehyde CHO-087 CHO-088 CHO-089 3-4-Dimecthytrueno(b)thiopriene3-Bromothiophene-2-carboxalde 6-Bromo-2-hydroxy-3-methoxyo2-carboxaldehyde hyde enzaldehyde CHO-090 CHO-091 CHO-0925-Methylfurfural 3-Methyl-1H-Pyrazole-5-carboxa 5-Iodo-2-furaldehydeldehyde CHO-093 CHO-094 CHO-095 6-Methoxy-4-methylsalicylalden Ethyl4-Ethyl-5-formy-3-methyl-2-pyrro yde 2,4-Dimethyl-5-formy-3-pyrroleclecarboxylic acid CHO-096 CHO-097 CHO-098 Ethyl-5-formy-1,2,4-methyl-3-p4-(4-Formylpiperazine-1-yl)benz 4,4-Formylmorphorono-1-yl)benyrrolecarboxylate/ aldehyde zaldehyde CHO-099 CHO-100 CHO-1015-Chloro-3-methoxycarbonyl-4- 1-(4-chlorobenzyl)-4-bromo-pyraimidazole-4-carboxaldehyde methoxycarbonylmethyl-pyrrole-zole-5-carboxaldehyde 2-carboxaldehyde CHO-102 CHO-103 CHO-1044-Chloro-pyrazole-5-carboxalde 5-Ethoxycarbonyl-4-methyl-3-me5-t-Butyl-4-Hydroxy-3-iodoobenzal hyde thylcarbonyl-pyrrole-2-carboxalddehyde ehyde CHO-105 CHO-106 CHO-107 5-Bromofuran-2-carboxyaldehyde1,4-Dimethyl-3-formylcarbazole 1,4-Dihydroxy-2-formyl1,5,6,7,8,tetrahydronaphthalene CHO-108 CHO-109 CHO-110 5-fluoroisatin3,4-dimethyl-2-formylphrrole isatin CHO-111 CHO-112 CHO-1135-ethyl-2-formylthiophene 4-methoxybenzaldehyde4-diethylaminobenzaldehyde CHO-114 CHO-115 CHO-1163,5-diethylpyrrole-2-carboxalden 5-Benzyloxyindole-3-carboxalde3-Bromo-5-chloro-2-hydroxyben yde hyde zaldehyde CHO-117 CHO-118 CHO-1192-(4-chlorohpenylthio)benzalden 6-chloropipercnalChromcne-3-carboxaldehyde yde CHO-120 CHO-121 CHO-1223-Cyanobenzaldehyde 4-Cyanobenzaldehyde 6,8-Dichloroanromone-3-carboxaldehyde CHO-123 CHO-124 CHO-125 2,5-ethydroxybenzaldehyde2,3-Dimethoxybenzaldehyde 2,4-Dimethoxybenzaldehyde CHO-126 CHO-127CHO-128 2,5-Dimethoxybenzaldehyde 2,6-Dimethoxybenzaldehyde3,5-Dimethoxybenzaldehyde CHO-129 CHO-130 CHO-1314-Dimethyliamino-2-methoxyben 3,4-Dimethylbenzaldehyde5,7-Dimethylchromone-3-carbox zaldehyde aldehyde CHO-132 CHO-133 CHO-1345-Ethylfurural Ferrocenecarboxaldehyde Fkyirebe-2-carboxaldehyde CHO-135CHO-136 CHO-137 2-Fluoro-3-(trifluoroemethyl)benz2-Fluoro-4-(trifluoromethyl)benz 2-Fluoro-5-(trifluoromethyl)benzaldehyde aldehyde aldehyde CHO-138 CHO-139 CHO-1402-Fluoro-6-(trifluoromethyl)benz 2-Formylphenoxyacetic acid3-Methoxy-5-methylenedioxybe aldehyde nzaldehyde CHO-141 CHO-142 CHO-1432-Methoxy-1-naphthaldehyde 4-Methoxy-1-naphthaldehyde4-(Methylthio)benzaldehyde CHO-144 CHO-145 CHO-1463-Methylthioonene-2-carboxalde 5-Methylthioprene-2-carboxaldepentamedrylbenzaldehyde hyde hyde CHO-147 CHO-148 CHO-1493-Phenoxybenzaldehyde Pyridine-2-carboxaldehydePyridine-3-carboxaldehyde CHO-150 CHO-151 CHO-152Pyridine-4-carboxaldehyde 4-Pyrrolidinobenzaldehyde,1,2,3,6-Tetrahydrobenzaldehyde CHO-153 CHO-154 CHO-1552,3,4-Trimethoxybenzaldehyde 2,4,5-Trimethoxybenzaldehyde2,4,6-Trimethoxybenzaldehyde CHO-156 CHO-157 CHO-1583,4,5-Trimethoxybenzaldehyde 1-Acetyl-3-indolecarboxaldehyd6-Chloro-3-formylchromone e CHO-159 CHO-160 CHO-1616-Chloro-3-formyl-7-methylchlo 5-(2-Chlorophenyl)furfural2-Chloro-3-quinoinecarboxalden mone yde CHO-162 CHO-163 CHO-1646,8-Dibromo-3-formylchromone 2,5-Dimethoxy-3-tetrahydrofurac4,5-Dimethyl-2-furaldehyde arboxaldehyde CHO-165 CHO-166 CHO-1679-Ethyl-3-carbazolecarboxalden 3-Formyl-6,7-clmethychromone3-formyl-6,8-dimethychromone yde CHO-168 CHO-169 CHO-1703-formyl-6-isoprophlchromone 3-formyl-6-methylchromone3-formyl-6-nitrochromone CHO-171 CHO-172 CHO-173 6-Formyluracil5-Methoxyindole-3-carboxalden 1-Methylisatin yde CHO-174 CHO-175 CHO-1765-(2-Nitrophenyl)furfural (S)-(.)-Perillaldehyde2-(Trifluoroacetyl)thiophene CHO-177 CHO-178 CHO-1793,5-diisopropyl-4-methoxybenzal 4-benzyloxy-3,5-diisoproplbenz3-t-butyl-4-methoxybenzaldehyd dehyde aldehyde e CHO-180 CHO-181 CHO-1824-benzyloxy-3-t-butylbenzaldeny 3-bromo-5-t-butyl-4-methoxyben4-benzyloxy-3-bromo-5-t-butylbe de zaldehyde nzaldehyde CHO-183 CHO-184CHO-185 3-t-butyl-5-chloro-4-methoxyben 4-benzyloxy-3-t-butyl-5-chlorooe3-t-butyl-5-ioco-4-methoxybenza zaldehyde nzaldehyde ldehyde CHO-186CHO-187 CHO-188 4-benzyloxy-3-t-butyl-5-iodoben3-t-butyl-4-methoxy-5-nitrobenza 4-benzyloxy-3-t-butyl-5-nitrobenzaldehyde ldehyde zaldehyde CHO-189 CHO-190 CHO-1913,5-di-t-butyl-4-methoxybenzald 4-benzyloxy-3,5-di-t-butylbenzal3,5-dimethyl-4-methoxybenzald ehyde dehyde enyde CHO-192 CHO-193 CHO-1944-oenzyloxy-3,5-dimethylbenzal 5-bromo-2-hydroxy-3-methoxy-o5-bromosalicyaldehyde 201 dehyde enzaldehyde CHO-195 CHO-196 CHO-1972-hydroxy-5-nitrobenzaldehyde 4-hydroxy-2-nitro-3-methoxybe3-ethoxysalicyaldehyde nzaldehyde CHO-198 CHO-199 CHO-2003,5-clchlorosalicylaldehyde 5-chlorosalicyaldehyde4-(diethylamin)salicyaldehyde CHO-201 CHO-202 CHO-2035-(trifluoromethoxy)salicylaldehy 3,5-dibromosalicyaldehyde3-fluorosalicyaldehyde de CHO-204 CHO-205 CHO-2063-bromo-4-hydroxybenzaldehyd 5-chlorosalicyaldehyde2-4,dimethyl-5-formylpyrrole e CHO-207 CHO-208 CHO-2093,5-diisopropyl-2-formylpyrrole 3,5-dimethylthlophene-2-carbox3-methyl-5-ethylthiophene-2-car aldehyde boxaldehyde CHO-210 CHO-211CHO-212 3-methyl-5-isopropylthiophene-2 3-methyl-5-cyclopentylmethylthi3-methyl-5-cycloproptlthiophene -carboxaldehyde ophene-2-carboxaldehyde-2-carboxaldehyde CHO-213 CHO-214 CHO-2154-methyl-5-ethylthiophene-2-car 4-methyl-5-isoproptlthiophene-24-methyl-5-cyclopentylmethylthi boxaldehyde -carboxaldehydeophene-2-carboxaldehyde CHO-216 CHO-217 CHO-2184-methyl-5-cyclopropylmethylthi 5-isopropylthiophene-2-carboxal5-phenylmethylthiophene-2-carb ophene-2-carboxaldehyde dehyde oxaldehydeCHO-219 CHO-220 CHO-221 5-cydlohexylmethylthiophene-2-5-cyclohexylthiophene-2-carbox 5-phenylthiophene-2-carboxaldecarboxaldehyde aldehyde hyde CHO-222 CHO-223 CHO-2243-methyl-5-propylthiophene-2-ca 3-methyl-5-cyclohexylmethylthio4-methyl-5-propylthiophene-2-ca rboxaldehyde phene-2-carboxaldehyderboxaldehyde CHO-225 CHO-226 CHO-227 4-methyl-5-cyclohexyimethylthio5-n-butylthiophene-2-carboxalde 5-cyclopropylmethylthiophene-2-phene-2-carboxaldehyde hyde carboxaldehyde CHO-228 CHO-229 CHO-2305-cyclopropylthiophene-2-carbo 3-methyl-5-phenylmethylthiophe4-methyl-5-phenylmethylthiophe xaldehyde ne-2-carboxaldehydene-2-carboxaldehyde CHO-231 CHO-232 CHO-2335-cyclopentylmethylthiophene-2- 5-cyclopentylthiophene-2-carbox4,5-dimethylthiophene-2-carobx carboxaldehyde aldehyde aldehyde CHO-234CHO-235 CHO-236 5-n-propylthiophene-2-carboxaldehyde CHO-237

[0621] TABLE 13 MASTER PLATE PLATE BARCODE ROW COLUMN NAME 10717 A 23-(2-ethoxybenzylidenyl)-5,7- dibromo-2-indolinone 10717 A 33-[(thien-2-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10717 A 43-[(1-methylpyrrol-2-yl)methyl- idenyl]-5,7-dibromo-2-indolinone 10717 A5 3-(4-fluorobenzylidenyl)-5,7- dibromo-2-indolinone 10717 A 63-[(indol-3-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10717 A 73-[(2-methylthien-5-yl)methyl- idenyl]-5)7-dibromo-2-indolinone 10717 A8 3-(4-bromobenzylidenyl)-5,7- dibromo-2-indofinone 10717 A 93-[(pyrrol-2-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10717 A 10 3-(2-hydroxy-6-methoxybenzyl- idenyl)-5,7-dibromo-2-indolinone 10717 A11  3-[(3)4-dibromo-2-methylpyrrol- 5-yl)methylidenyl]-5,7-dibromo-2-indolinone 10717 B 2 3-(2-ethoxybenzylidenyl)-5-iodo- 2-indolinone10717 B 3 3-[(thien-2-yl)methylidenyl]- 5-iodo-2-indolinone 10717 B 43-[(1-methylpyrrol-2-yl)methyl- idenyl]-5-iodo-2-indolinone 10717 B 53-(4-fluorobenzylidenyl)-5-iodo- 2-indolinone 10717 B 63-[(indol-3-yl)methylidenyl]- 5-iodo-2-indolinone 10717 B 73-[(2-methylthien-5-yl)methyl- idenyl]-5-iodo-2-indolinone 10717 B 83-(4-bromobenzylidenyl)-5-iodo- 2-indolinone 10717 B 93-[(pyrrol-2-yl)methylidenyl]- 5-iodo-2-indolinone 10717 B 10 3-(2-hydroxy-6-methoxybenzyl- idenyi)-5-iodo-2-indolinone 10717 B 11 3-[(3,4-dibromo-2-methylpyrrol- 5-yl)methylidenyl]-5-iodo-2- indolinone10717 C 2 3-(2-ethoxybenzylidenyl)-5-bromo- 4-methyl-2-indolinone 10717C 3 3-[(thien-2-yl)methylidenyl]- 5-bromo-4-methyl-2-indolinone 10717 C4 3-[(1-methylpyrrol-2-yl)methyl- idenyl)-5-bromo-4-methyl-2- indolinone10717 C 5 3-(4-fluorobenzylidenyl)-5-bromo- 4-methyl-2-indolinone 10717C 6 3-[(indol-3-yl)methylidenyl]- 5-bromo-4-methyl-2-indolinone 10717 C7 3-[(2-methylthien-5-yl)methyl- idenyl]-5-bromo-4-methyl-2- indolinone10717 C 8 3-(4-bromobenzylidenyl)-5-bromo- 4-methyl-2-indolinone 10717 C9 3-[(pyrrol-2-yl)methylidenyl]- 5-bromo-4-methyl-2-indolinone 10717 C10  3-(2-hydroxy-6-methoxybenzyl- idenyl)-5-bromo-4-methyl-2- indolinone10717 C 11  3-[(3,4-dibromo-2-methylpyrrol-5-yl)methylidenyl]-5-bromo-4- methyl-2-indolinone 10717 D 23-(2-ethoxybenzylidenyl)-5-methyl- aminosulfonyl-2-indolinone 10717 D 33-[(thien-2-yl)methylidenyl- 5-methylaminosulfonyl-2-indolinone 10717 D4 3-[(1-methylpyrrol-2-yl)methyl- idenyl]-5-methylaminosulfonyl-2-idolinone 10717 D 5 3-(4-fluorobenzylidenyl)-5-methyl-aminosulfonyl-2-indolinone 10717 D 6 3-[(indol-3-yl)methylidenyl-5-methylaminosulfonyl-2-indolinone 10717 D 73-[(2-methylthien-5-yl)methyl- idenyi]-5-methylaminosulfonyl-2-indolinone 10717 D 8 3-(4-bromobenzylidenyl)-5-methyl-aminosulfonyl-2-indolinone 10717 D 9 3-[(pyrrol-2-yl)methylidenyl]-5-methylaminosulfonyl-2-indolinone 10717 D 10 3-(2-hydroxy-6-methoxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10717 D 11  3-[(3,4-dibromo-2-methylpyrrol-5-yl)methylideny]-5-methyl- aminosulfonyl-2-indolinone 10717 E 23-(2-ethoxybenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10717 E 3 3-[(thien-2-yl)methylidenyl]-5-[4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10717 E 43-[(1-methylpyrrol-2-yl)methyl- idenyl]-5-[4-(trifluoromethyl)phenylaminosulfonyl]-2-indolinone 10717 E 53-(4-fluorobenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10717 E 6 3-[(indol-3-yl)methylidenyl]-5-[4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10717 E 73-[(2-methylthien-5-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10717 E 83-(4-bromobenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10717 E 9 3-[(pyrrol-2-yl)methylidenyl]-5-(4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10717 E 10 3-(2-hydroxy-6-methoxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]2-indolinone 10717 E 11 3-[(3,4-dibromo-2-methylpyrrol- 5-yl)methylidenyl]-5-[4-(tri-fluoromethyl)phenylaminosulfonyl]- 2-indolinone 10717 F 23(2-ethoxybenzylidenyl)-5- (morpholin-1-yl)sulfonyl-2- indolinone 10717F 3 3[(thien-2-yl)methylidenyl]- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10717 F 4 3[(1-methylpyrrol-2-yl)methyl-idenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10717 F 53-(4-fluorobenzylidenyl)-5- (morpholin-1-yl)sulfonyl-2- indolinone 10717F 6 3-[(indol-3-yl)methylidenyl]- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10717 F 7 3-[(2-methylthien-5-yl)methyl-idenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10717 F 83-(4-bromobenzylidenyl)-5- (morpholin-1-yl)sulfonyl-2- indolinone 10717F 9 3-[(pyrrol-2-yl)methylidenyl]- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10717 F 10  3-(2-hydroxy-6-methoxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10717 F 11 3-[(3,4-dibromo-2-methylpyrrol- 5-yl)methylidenyl]-5-(morpholin-1-yl)sulfonyl-2-indolinone 10717 G 2 3-(2-ethoxybenzylidenyl)-5-(2-chloroethyl-2-indolinone 10717 G 3 3[thien-2-yl)methylidenyl]-5-(2-chloroethyl)-2-indolinone 10717 G 4 3[(1-methylpyrrol-2-yl)methyl-idenyl]-5-(2-chloroethyl)-2- indolinone 10717 G 53-(4-fluorobenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10717 G 63-[(indol-3-yl)methylidenyl]- 5-(2-chloroethyl)-2-indolinone 10717 G 73-[(2-methylthien-5-yl)methyl- idenyl]-5-(2-chloroethyl)-2- indolinone10717 G 8 3-(4-bromobenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10717G 9 3-[(pyrrol-2-yl)methylidenyl]- 5-(2-chloroethyl)-2-indolinone 10717G 10  3-(2-hydroxy-6-methoxybenzyl- idenyl)-5-(2-chloroethyl)-2-indolinone 10717 G 11  3-[(3,4-dibromo-2-methylpyrrol-5-yl)methylidenyl]-5-(2- chloroethyl)-2-indolinone 10718 A 23-[(2,4-dimethyl-3-ethoxy- carbonylpyrrol-5-yl)methyl-idenyl]-5,7-dibromo-2- indolinone 10718 A 33-(3-bromo-2-hydroxy-5-methoxy- benzylidenyl)-5,7-dibromo-2- indolinone10718 A 4 3[(1-hydroxynapth-2-yl)- methylidenyl]-5,7-dibromo-2-indolinone 10718 A 5 3-[[2-ethoxycarbonyl-3-(2-ethoxycarbonyl)ethyl-4-(ethoxy- carbonylmethyl)pyrrol-5-yl]-methylidenyl]-5,7-dibromo-2- indolinone 10718 A 63-[(2-methyl-3-ethoxycarbonyl- furan-5-yl)methylidenyl]-5,7-dibromo-2-indolinone 10718 A 7 3-[(2,3-dimethoxycarbonyl-5-methylpyrrol-4-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10718 A 83-(4-chloro-3-nitrobenzylidenyl)- 5,7-dibromo-2-indolinone 10718 A 93-(2,4-dihydroxy-3-methylbenzyl- idenyl)-5,7-dibromo-2- indolinone 10718A 10  3-[(furan-2-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10718 A 11 3-[(nitrofuran-5-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10718 B 23-[(2,4-dimethyl-3-ethoxy- carbonylpyrrol-5-yl)methyl-idenyl]-5-iodo-2-indolinone 10718 B 3 3-(3-bromo-2-hydroxy-5-methoxy-benzylidenyl)-5-iodo-2-indolinone 10718 B 43-[(1-hydroxynapth-2-yl)methyl- idenyl]-5-iodo-2-indolinone 10718 B 53-[[2-ethoxycarbonyl-3-(2- ethoxycarbonyl)ethyl-4-(ethoxy-carbonylmethyl)pyrrol-5-yl]methyl- idenyl]-5-iodo-2-indolinone 10718 B 63-[(2-methyl-3-ethoxycarbonyl- furan-5-yl)methylidenyl]-5-iodo-2-indolinone 10718 B 7 3-[(2,3-dimethoxycarbonyl-5-methylpyrrol-4-yl)methydenyl]-5- iodo-2-indolinone 10718 B 83-(4-chloro-3-nitrobenzylidenyl)- 5-iodo-2-indolinone 10718 B 93-(2,4-dihydroxy-3-methylbenzyl- idenyl)-5-iodo-2-indolinone 10718 B 10 3-[(furan-2-yl)methylidenyl]- 5-iodo-2-indolinone 10718 B 11 3-[(2-nitrofuran-5-yl)methyl- idenyl-5-iodo-2-indolinone 10718 C 23-[(2,4-dimethyl-3-ethoxy- carbonylpyrol-5-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10718 C 33-(3-bromo-2-hydroxy-5-methoxy- benzylidenyl)-5-bromo-4-methyl-2-indolinone 10718 C 4 3-[(1-hydroxynapth-2-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10718 C 53-[[2-ethoxycarbonyl-3-(2- ethoxycarbonyl)ethyl-4-(ethoxy-carbonylmethyl)pyrrol-5-yl]- methylidenyl]-5-bromo-4-methyl-2-indolinone 10718 C 6 3-[(2-methyl-3-ethoxycarbonyl-furan-5-yl)methylidenyl]-5-bromo- 4-methyl-2-indolinone 10718 C 73-[(2,3-dimethoxycarbonyl-5- methylpyrrol-4-yl)methylidenyl]-5-bromo-4-methyl-2-indolinone 10718 C 83-(4-chloro-3-nitrabenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10718 C9 3-(2,4-dihydroxy-3-methylbenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10718 C 10  3-[(furan-2-yl)methylidenyil-5-bromo-4-methyl-2-indolinone 10718 C 11 3-[(2-nitrofuran-5-yl)methylidenyl]- 5-bromo-4-methyl-2-indolinone 10718D 2 3-[(2,4-dimethyl-3-ethoxycarbonyl- pyrrol-5-yl)methylidenyl]-5-methylaminosulfonyl-2-indolinone 10718 D 33-(3-bromo-2-hydroxy-5-methoxy- benzylidenyl)-5-methylamino-sulfonyl-indolinone 10718 D 4 3-[(1-hydroxynapth-2-yl)methyl-idenyl]-5-methylaminosulfonyl- 2-indolinone 10718 D 53-[[2-ethoxycarbonyl-3-(2-ethoxy- carbonyl)ethyl-4-(ethoxycarbonyl-methyl)pyrrol-5-yl]methylidenyl]- 5-methylaminosulfonyl-2-indolinone10718 D 6 3-[(2-methyl-3-ethoxycarbonyl-furan-5-yl)methylidenyl]-5-methyl- aminosulfonyl-2-indolinone 10718 D 73-[(2,3-dimethoxycarbonyl-5- methylpyrrol-4-yl)methylidenyl]-5-methylaminosulfonyl-2-indolinone 10718 D 83-(4-chloro-3-nitrobenzylidenyl)-5- methylaminosulfonyl-2-indolinone10718 D 9 3-(2,4-dihydroxy-3-methylbenzyl-idenyl)-5-methylaminosulfonyl-2- indolinone 10718 D 10 3-[(furan-2-yl)methylidenyl]-5- methylaminosulfonyl-2-indolinone 10718 D11  3-[(2-nitrofuran-5-yl)methylidenyl]-5-methylaminosulfonyl-2-indolinone 10718 E 23-[(2,4-dimethyl-3-ethoxycarbonyl- pyrrol-5-yl)methylidenyl]-5-[4-(trifluoromethyl)phenylamino- sulfonyl-2-indolinone 10718 E 33-(3-bromo-2-hydroxy-5-methoxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10718 E 43-[(1-hydroxynapth-2-yl)methyl- idenyi]-5-[4-(trifluoromethyl)-phenylaminosulfonyl-2-indolinone 10718 E 53-[(2-ethoxycarbonyl-3-(2-ethoxy- carbonyl)ethyl-4-ethoxycarbonyl-methyl-pyrrol-5-yl)methylidenyl]- 5-[4-(trifluoromethyl)phenylamino-sulfonyl-2-indolinone 10718 E 6 3-[(2-methyl-3-ethoxycarbonyl-furan-5-yl)methylidenyl]-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10718 E 7 3-[(2,3-dimethoxycarbonyl-5-methylpyrrol-4-yl)methylidenyl]- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl-2-indolinone 10718 E 8 3-(4-chloro-3-nitrobenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10718 E 93-(2,4-dihydroxy-3-methylbenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl-2-indolinone 10718 E 10 3-[(furan-2-yl)methylidenyl]- 5-]4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indoinone 10718 E 11  3-[(2-nitrofuran-5-yl)methyl-idenyl]-5-[4-(trifluoromethyl)- phenylaminosulfonyl]-2-indolinone 10718F 2 3-[(2,4-dimethyl-3-ethoxycarbonyl- pyrrol-5-yl)methylidenyl]-5-(morpholin-1-yl)sulfonyl-2- indolinone 10718 F 33-(3-bromo-2-hydroxy-5-methoxy- benzylidenyl)-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10718 F 4 3-[(1-hydroxynapth-2-yl)methyl-idenyl]-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10718 F 53-[[2-ethoxycarbonyl-3-(2-ethoxy- carbonyl)ethyl-4-(ethoxycarbonyl-methyl)pyrrol-5-yl]methylidenyl]- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10718 F 6 3-[(2-methyl-3-ethoxycarbonyl-furan-5-yl)methylidenyl]-5- (morpholin-1-yl)sulfonyl-2- indolinone 10718F 7 3-[(2,3-dimethoxycarbonyl-5- methyl-pyrrol-4-yl)methylidenyl]-5-(morpholin-1-yl)sulfonyl-2- indolinone 10718 F 83-(4-chloro-3-nitrobenzylidenyl)- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10718 F 9 3-(2,4-dihydroxy-3-methylbenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10718 F 10 3-[(furan-2-yl)methylidenyl]-5- (morpholin-1-yl)sulfonyl-2- indolinone10718 F 11  3-[(2-nitrofuran-5-yl)methyl-idenyl]-5-(morpholin-1-yl-sulfonyl- 2-indolinone 10718 G 23-[(2,4-dimethyl-3-ethoxy- carbonylpyrrol-5-yl)methylidenyi]-5-(2-chloroethyl)-2-indolinone 10718 G 3 3-(3-bromo-2-hydroxy-5-methoxy-benzylidenyl)-5-(2-chloroethyl)- 2-indolinone 10718 G 43-[(1-hydroxynapth-2-yl)methyl- idenyl]-5-(2-chloroethyl)-2- indolinone10718 G 5 3-[[2-ethoxycarbonyl-3-(2-ethoxy-carbonyl)ethyl-4(ethoxycarbonyl- methyl)pyrrol-5-yl]methylidenyl]-5-(2-chloroethyl)-2-indolinone 10718 G 6 3-[(2-methyl-3-ethoxycarbonyl-furan-5-yl)methylideny]3-5-(2- chloroethyl)-2-indolinone 10718 G 73-[(2,3-dimethoxycarbonyl-5-methyl- pyrrol-4-yl)methylidenyl]-5-(2-chloroethyl)-2-indolinone 10718 G 8 3-(4-chloro-3-nitrobenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10718 G 93-(2,4-dihydroxy-3-methylbenzyl- idenyl)-5-(2-chloroethyl)-2- indolinone10718 G 10  3-[(furan-2-yl)methylidenyl]-5- (2-chloroethyl)-2-indolinone10718 G 11  3-[(2-nitrofuran-5-yl)methylidenyl]-5-(2-chloroethyl)-2-indolinone 10719 A 23-(4-ethoxy-3-methoxybenzylidenyl)- 5,7-dibromo-2-indolinone 10719 A 33-(3,4-dihydoxybenzylidenyl)-5,7- dibromo-2-indolinone 10719 A 43-(2,4-dimethoxybenzylidenyl)-5,7- dibromo-2-indolinone 10719 A 53-[(2,4-dimethyl-3-ethylpyrrol-5-yl) methylidenyl]-5,7-dibromo-2-indolinone 10719 A 6 3-(2,4,6-trimethoxybenzylidenyl)-5,7-dibromo-2-indolinone 10719 A 7 3-(4-hydroxybenzylidenyl)-5,7-dibromo-2-indolinone 10719 A 8 3-(4-dimethylaminobenzylidenyl)-5,7-dibromo-2-indolinone 10719 A 9 3-(2-chloro-4-fluorobenzylidenyl)-5,7-dibromo-2-indolinone 10719 A 10  3-(3-nitrobenzylidenyl)-5,7-dibromo-2-indolinone 10719 A 11  3-[4-fluoro-2-(trifluoromethyl)-benzylidenyl]-5,7-dibromo-2- indolinone 10719 B 23-(4-ethoxy-3-methoxybenzylidenyl)- 5-iodo-2-indolinone 10719 B 33-(3,4-dihydoxybenzyldenyl)-5- iodo-2-indolinone 10719 B 43-(2,4-dimethoxybenzylidenyl)- 5-iodo-2-indolinone 10719 B 53-[(2,4-dimethyl-3-ethylpyrrol- 5-yl)methylidenyl]-5-iodo-2- indolinone10719 B 6 3-(2,4,6-trimethoxybenzylidenyl)- 5-iodo-2-indolinone 10719 B7 3-(4-hydroxybenzylidenyl)-5-iodo- 2-indolinone 10719 B 83-(4-dimethylaminobenzylidenyl)- 5-iodo-2-indolinone 10719 B 93-(2-chloro-4-fluorobenzylidenyl)- 5-iodo-2-indolinone 10719 B 10 3-(3-nitrobenzyldenyl)-5-iodo- 2-indolinone 10719 B 11 3-[4-fluoro-2-(trifluoromethyl)- benzylidenyi[-5-iodo-2- indolinone10719 C 2 3-(4-ethoxy-3-methoxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10719 C 3 3-(3,4-dihydoxybenzylidenyl)-5-bromo-4-methyl-2-indolinone 10719 C 4 3-(2,4-dimethoxybenzylidenyl)-5-bromo-4-methyl-2-indolinone 10719 C 5 3-[(2,4-dimethyl-3-ethylpyrrol-5-yl)methylidenyl]-5-bromo-4- methyl-2-indolinone 10719 C 63-(2,4,6-trimethoxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10719 C7 3-(4-hydroxybenzylidenyl)-5- bromo-4-methyl-2-indolinone 10719 C 83-(4-dimethylaminobenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10719 C 93-(2-chloro-4-fluorobenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10719 C10  3-(3-nitrobenzylidenyl)-5-bromo- 4-methyl-2-indolinone 10719 C 11 3-[4-fluoro-2-(trifluoromethyl)- benzylidenyl]-5-bromo-4-methyl-2-indolinone 10719 D 2 3-(4-ethoxy-3-methoxybenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10719 D 33-(3,4-dihydoxybenzylidenyl)-5- methylaminosulfonyl-2-indolinone 10719 D4 3-(2,4-dimethoxybenzyhdenyl)-5- methylaminosulfonyl-2-indolinone 10719D 5 3-[(2,4-dimethyl-3-ethylpyrrol- 5-yl)methylidenyl]-5-methyl-aminosulfonyl-2-indolinone 10719 D 6 3-(2,4,6-trimethoxybenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10719 D 73-(4-hydroxybenzylidenyl)-5-methyl- aminosulfonyl-2-indolinone 10719 D 83-(4-dimethylaminobenzylidenyl)-5- methylaminosulfonyl-2-indolinone10719 D 9 3-(2-chloro-4-fluorobenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10719 D 10 3-(3-nitrobenzylidenyl)-5-methyl- aminosulfonyl-2-indolinone 10719 D 11 3-[4-fluoro-2-(trifluoromethyl)- benzylidenyl]-5-methylamino-sulfonyl-2-indolinone 10719 E 2 3-(4-ethoxy-3-methoxybenzylidenyl)-5-(4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10719 E 33-(3,4-dihydoxybenzylidenyl)-5- [4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10719 E 4 3-(2,4-dimethoxybenzylidenyl)-5-[4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10719 E 53-[(2,4-dimethyl-3-ethylpyrrol-5- yl)methylidenyl]-5-(4-(trifluoro-methyl)phenylaminosulfonyl]-2- indolinone 10719 E 63-(2,4,6-trimethoxybenzylidenyl)-5- [4-(trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10719 E 7 3-(4-hydroxybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10719 E 83-(4-dimethylaminobenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10719 E 9 3-(2-chloro-4-fluorobenzylidenyl)-5-[4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10719 E 10 3-(3-nitrobenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10719 E 11  3-[4-fluoro-2-(trifluoromethyl)-benzylidenyl]-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10719 F 2 3-(4-ethoxy-3-methoxybenzylidenyl)-5-(morpholin-1-yl)sulfonyl-2- indolinone 10719 F 33-(3,4-dihydoxybenzylidenyl)-5- (morphol-1-yl)sulfonyl-2-indolinone10719 F 4 3-(2,4-dimethoxybenzylidenyl)-5- (morpholin-1-yl)sulfonyl-2-indolinone 10719 F 5 3[(2,4-dimethyl-3-ethylpyrrol-5-yl)methylidenyl]5-(morpholin-1-yl)- sulfonyl-2-indolinone 10719 F 63-(2,4,6-trimethoxybenzylidenyl)-5- (morpholin-1-yl)sulfonyl-2-indolinone 10719 F 7 3-(4-hydroxybenzylidenyl)-5-(morpholin-1-yl)sulfonyl-2-indolinone 10719 F 83-(4-dimethylaminobenzylidenyl)-5- (molpholin-1-yl)sulfonyl-2-indolinone10719 F 9 3-(2-chloro-4-fluorobenzylidenyl)-5-(morpholin-1-yl)sulfonyl-2-indolinone 10719 F 10 3-(3-nitrobenzylidenyl)-5-(morpholin- 1-yl)sulfonyl-2-indolinone 10719 F11  3-[4-fluoro-2-(trifluoromethyl)- benzylidenyl]-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10719 G 2 3-(4-ethoxy-3-methoxybenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10719 G 33-(3,4-dihydoxybenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10719 G 43-(2,4-dimethoxybenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10719 G 53-[(2,4-dimethyl-3-ethylpyrrol-5-yl)- methylidenyl]-5-(2-chloroethyl)-2-indolinone 10719 G 6 3-(2,4,6-trimethoxybenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10719 G 7 3-(4-hydroxybenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10719 G 8 3-(4-dimethylaminobenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10719 G 93-(2-chloro-4-fluorobenzylidenyl)- 5-(2-chloroethyl)-2-indolinone 10719G 10  3-(3-nitrobenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10719 G11  3-[4-fluoro-2-(trifluoromethyl)- benzylidenyl]-5-(2-chloroethyl)-2-indolinone 10720 A 2 3-(2,4,6-trifluorobenzylidenyl)-5,7-dibromo-2-indolinone 10720 A 3 3-(4-hydroxy-2-methoxybenzylidenyl)-5,7-dibromo-2-indolinone 10720 A 4 3-(3,4-dimethoxybenzylidenyl)-5,7-dibromo-2-indolinone 10720 A 5 3-(2-hydroxybenzylidenyl)-5,7-dibromo-2-indolinone 10720 A 6 3-benzylidenyl-5,7-dibromo-2- indolinone10720 A 7 3-[(2-methylmercaptothien-5-yl)- methylidenyl]-5,7-dibromo-2-indolinone 10720 A 8 3-(2,4-dihydroxy-6-methylbenzyl-idenyl)-5,7-dibromo-2-indolinone 10720 A 93-(3-ethoxy-4-hydroxybenzylidenyl)- 5,7-dibromo-2-indolinone 10720 A 10 3-(2-hydroxy-5-methoxybenzylidenyl)- 5,7-dibromo-2-indolinone 10720 A11  3-[imidazol-2-yl)methylienyl]- 5,7-dibromo-2-indolinone 10720 B 23-(2,4,6-trifluorobenzylidenyl)-5- iodo-2-indolinone 10720 B 33-(4-hydroxy-2-methoxybenzylidenyl)- 5-iodo-2-indolinone 10720 B 43-(3,4-dimethoxybenzylidenyl)-5- iodo-2-indolinone 10720 B 53-(2-hydroxybenzylidenyl)-5-iodo- 2-indolinone 10720 B 63-benzylidenyl-5-iodo-2- indolinone 10720 B 73-[(2-methylmercaptothien-5-yl) methylidenyl]-5-iodo-2-indolinone 10720B 8 3-(2,4-dihydroxy-6-methylbenzylidenyl)- 5-iodo-2-indolinone 10720 B9 3-(3-ethoxy-4-hydroxybenzylidenyl)- 5-iodo-2-indolinone 10720 B 10 3-(2-hydroxy-5-methoxybenzylidenyl)- 5-iodo-2-indolinone 10720 B 11 3-[(imidazol-2-yl)methylidenyl-5- iodo-2-indolinone 10720 C 23-(2,4,6-trifluorobenzylidenyl)-5- bromo-4-methyl-2-indolinone 10720 C 33-(4-hydroxy-2-methoxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10720C 4 3-(3,4-dimethoxybenzylidenyl)-5- bromo-4-methyl-2-indolinone 10720 C5 3-(2-hydroxybenzylidenyl)-5- bromo-4-methyl-2-indolinone 10720 C 63-benzylidenyl-5-bromo-4-methyl- 2-indolinone 10720 C 73[(2-methylmercaptothien-5-yl)- methylidenyl]-5-bromo-4-methyl-2-indolinone 10720 C 8 3-(2,4-dihydroxy-6-methylbenzyl-idenyl)-5-bromo-4-methyl-2- indolinone 10720 C 93-(3-ethoxy-4-hydroxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10720C 10  3-(2-hydroxy-5-methoxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10720 C 11  3-[(imidazol-2-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10720 D 23-(2,4,6-trifluorobenzylidenyl)-5- methylaminosulfonyl-2-indolinone10720 D 3 3-(4-hydroxy-2-methoxybenzyl- idenyl)-5-methylamino-sulfonyl-2-indolinone 10720 D 4 3-(3,4-dimethoxybenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10720 D 5 3-(2-hydroxybenzylidenyl)-5-methylaminosulfonyl-2- indolinone 10720 D 63-benzylidenyl-5-methylamino- sulfonyl-2-indolinone 10720 D 73-[(2-methylmercaptothien- 5-yl)methylidenyl]-5-methylaminosulfonyl-2-indolinone 10720 D 8 3-(2,4-dihydroxy-6-methyl-benzylidenyl)-5-methylamino- sulfonyl-2-indolinone 10720 D 93-(3-ethoxy-4-hydroxybenzyl- idenyl)-5-methylaminosulfonyl- 2-indolinone10720 D 10  3-(2-hydroxy-5-methoxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10720 D 11  3-[(imidazol-2-yl)methyl-idenyl]-5-methylaminosulfonyl- 2-indolinone 10720 E 23-(2,4,6-trifluorobenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10720 E 3 3-(4-hydroxy-2-methoxybenzyl-idenyl)-5-[4-(trifluoromethyl)- phenylaminosulfonyl]-2-indolinone 10720E 4 3-(3,4-dimethoxybenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10720 E 5 3-(2-hydroxybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10720 E 63-benzylidenyl-5-[4-(trifluoro- methyl)phenylaminosulfonyl]-2-indolinone 10720 E 7 3-[(2-methylmercaptothien-5-yl)-methylidenyl]-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10720 E 8 3-(2,4-dihydroxy-6-methylbenzyl-idenyl)-5-[4-(trifluoromethyl)- phenylaminosulfonyl]-2-indolinone 10720E 9 3-(3-ethoxy-4-hydroxybenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10720 E 10 3-(2-hydroxy-5-methoxybenzylidenyl)- 5-[4-(trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10720 E 11  3-[(imidazol-2-yl)methylidenyl]-5-[4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10720 F 23-(2,4,6-trifluorobenzylidenyl)- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10720 F 3 3-(4-hydroxy-2-methoxybenzyl-idenyl)-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10720 F 43-(3,4-dimethoxybenzylidenyl)-5- (morpholin-1-yl)sulfonyl- 2-indolinone10720 F 5 3-(2-hydroxybenzylidenyl)-5- (morpholin-1-yl)sulfonyl-2-indolinone 10720 F 6 3-benzylidenyl-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10720 F 7 3-[(2-methylmercaptothien-5-yl)-methylidenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10720 F 83-(2,4-dihydroxy-6-methylbenzyl- idenyl)-5-(morpholin-1-yl)sulfonyl-2-indolinone 10720 F 9 3-(3-ethoxy-4-hydroxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl-2- indolinone 10720 F 10 3-(2-hydroxy-5-methoxybenzylidenyl)- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10720 F 11  3-[(imidazol-2-yl)methylidenyl]-5-(morpholin-1-yl)sulfonyl-2- indolinone 10720 G 23-(2,4,6-trifluorobenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10720 G3 3-(4-hydroxy-2-methoxybenzyl- idenyl)-5-(2-chloroethyl)-2- indolinone10720 G 4 3-(3,4-dimethoxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone10720 G 5 3-(2-hydroxybenzylidenyl)-5-(2- chloroethyl)-2-indolinone10720 G 6 3-benzylidenyl-5-(2-chloroethyl)- 2-indolinone 10720 G 73-[(2-methylmercaptothien-5-yl) methylidenyl]-5-(2-chloroethyl)-2-indolinone 10720 G 8 3-(2,4-dihydroxy-6-methyl benzylidenyl)-5-(2-chloroethyl)-2-indolinone 10720 G 93-(3-ethoxy-4-hydroxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10720G 10  3-(2-hydroxy-5-methoxybenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10720 G 11 3-[(imidazol-2-yl)methylidenyl]- 5-(2-chloroethyl)-2-indolinone 10721 A2 3-[(1-methylbenzimidazol-2-yl)- methylidenyl]-5,7-dibromo-2-indolinone 10721 A 3 3-[(4-chloro-1-methylpyrazol-3-yl)-methylidenyl]-5,7-dibromo-2- indolinone 10721 A 43-[(2,3-dimethylthien-5-yl)methyl- idenyl]-5,7-dibromo-2-indolinone10721 A 5 3-[(4,5,6,7-tetrahydroindol-2-yl)-methylidenyl]-5,7-dibromo-2- indolinone 10721 A 63-(3-chloromethyl-2-hydroxy-5-nitro- benzylidenyl)-5,7-dibromo-2-indolinone 10721 A 7 3-[(2-chlorothien-5-yl)methyl-idenyl]-5,7-dibromo-2-indolinone 10721 A 83-[(2,4-dimethylpyrrol-5-yl)methyl- idenyl]-5,7-dibromo-2-indolinone10721 A 9 3-(3-t-butyl-4-hydroxybenzylidenyl)- 5,7-dibromo-2-indolinone10721 A 10  3-(3-bromo-5-t-butyl-4-hydroxybenzyl-idenyl)-5,7-dibromo-2-indolinone 10721 A 11 3-(3,5-di-t-butyl-4-hydroxybenzyl- idenyl)-5,7-dibromo-2-indolinone10721 B 2 3-[(1-methylbenzimidazol-2-yl)-methylidenyl]-5-iodo-2-indolinone 10721 B 33-[(4-chloro-1-methylpyrazol-3-yl)- methylidenyl]-5-iodo-2-indolinone10721 B 4 3-[(2,3-dimethylthien-5-yl)methyl- idenyl]-5-iodo-2-indolinone10721 B 5 3-[(4,5,6,7-tetrahydroindol-2-yl)-methylidenyl]-5-iodo-2-indolinone 10721 B 63-(3-chloromethyl-2-hydroxy-5- nitrobenzylidenyl)-5-iodo-2- indolinone10721 B 7 3-[(2-chlorothien-5-yl)methylidenyl]- 5-iodo-2-indolinone10721 B 8 3-[(2,4-dimethylpyrrol-5-yl)methyl-idenyi]-5-iodo-2-indolinone 10721 B 93-(3-t-butyl-4-hydroxybenzylidenyl)- 5-iodo-2-indolinone 10721 B 10 3-(3-bromo-5-t-butyl-4-hydroxy- benzylidenyl)-5-iodo-2-indolinone 10721B 11  3-(3,5-di-t-butyl-4-hydroxybenzyl- idenyl]-5-iodo-2-indolinone10721 C 2 3-[(1-methylbenzimidazol-2-yl)-methylidenyl]-5-bromo-4-methyl- 2-indolinone 10721 C 33-[(4-chloro-1-methylpyrazol-3-yl)- methylidenyl]-5-bromo-4-methyl-2-indolinone 10721 C 4 3[(2,3-dimethylthien-5-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10721 C 53-[(4,5,6,7-tetrahydroindol-2-yl)- methylidenyl]-5-bromo-4-methyl-2-indolinone 10721 C 6 3-(3-chloromethyl-2-hydroxy-5-nitrobenzylidenyl)-5-bromo-4- methyl-2-indolinone 10721 C 73-[(2-chlorothien-5-yl)methylidenyl]- 5-bromo-4-methyl-2-indolinone10721 C 8 3-[(2,4-dimethylpyrrol-5-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10721 C 93-(3-t-butyl-4-hydroxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10721C 10  3-(3-bromo-5-t-butyl-4-hydroxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10721 C 11  3-(3,5-di-t-butyl-4-hydroxybenzyl-idenyl)-5-bromo-4-methyl-2- indolinone 10721 D 23-[(1-methylbenzimidazol-2-yl)- methylidenyl]-5-methylamino-/sulfonyl-2-indolinone 10721 D 3 3-[(4-chloro-1-methylpyrazol-3-yl)methylidenyl]-5-methylamino- sulfonyl-2-indolinone 10721 D 43-[(2,3-dimethylthien-5-yl) methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10721 D 5 3-[(4,5,6,7-tetrahydroindal-2-yl)-methylidenyl]-5-methylamino- sulfonyl-2-indolinone 10721 D 63-(3-chloromethyl-2-hydroxy- 5-nitrobenzylidenyl]-5-methyl-aminosulfonyl-2-indolinone 10721 D 7 3-[(2-chlorothien-5-yl)methyl-idenyl]-5-methylamino- sulfonyl-2-indolinone 10721 D 83-[(2,4-dimethylpyrrol-5-yl)- methylidenyi]-5-methylamino-sulfonyl-2-indolinone 10721 D 9 3-(3-t-butyl-4-hydroxybenzyl-idenyl)-5-methylamino- sulfonyl-2-indolinone 10721 D 10 3-(3-bromo-5-t-butyl-4-hydroxy- benzylidenyl)-5-methylamino-sulfonyl-2-indolinone 10721 D 11  3-(3,5-di-t-butyl-4-hydroxy-benzylidenyl)-5-methylamino- sulfonyl-2-indolinone 10721 E 23-[(1-methylbenzimidazol-2-yl)- methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10721 E 33-[(4-chloro-1-methylpyrazol-3-yl)- methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10721 E 43-[(2,3-dimethylthien-5-yl)- methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10721 E 53-[4,5,6,7-tetrahydroindol-2-yl)- methylidenyl]-5-[4-(triflouro-methyl)phenylaminosulfonyl]- 2-indolinone 10721 E 63-(3-chloromethyl-2-hydroxy-5- nitrobenzylidenyl)-5-[4-(tri-fluoromethyl)phenylamino- sulfonyl]-2-indolinone 10721 E 73-[(2-chlorothien-5-yl)methyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10721 E 83-[(2,4-dimethylpyrrol-5-yl)- methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10721 E 93-(3-t-butyl-4-hydroxybenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10721 E 10  3-(3-bromo-5-t-butyl-4-hydroxy-benzylidenyl)-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10721 E 11  3-(3,5-di-t-butyl-4-hydroxybenzyl-idenyl)-5-[4-(trifluoromethyl)- phenylaminosulfonyl]-2-indolinone 10721F 2 3-[(1-methylbenzimidazol-2-yl)- methylidenyl]-5-(morpholin-1-yl)-sulfonyl]-2-indolinone 10721 F 3 3-[(4-chloro-1-methylpyrazol-3-yl)-methylidenyl]-5-(morpholin-1-yl)- sulfonyl]-2-indolinone 10721 F 43-[(2,3-dimethylthien-5-yl)methyl- idenyl]-5-(morpholin-1-yl)sulfonyl]-2-indolinone 10721 F 5 3-[(4,5,6,7-tetrahydroindol-2-yl)-methylidenyl]-5-(morpholin-1-yl)- sulfonyl]-2-indolinone 10721 F 63-(3-chloromethyl-2-hydroxy-5- nitrobenzylidenyl)-5-(morpholin-1-yl)-sulfonyl]-2-indolinone 10721 F 7 3-[(2-chlorothien-5-yl)methyl-idenyl]-5-(morpholin-1-yl)- sulfonyl]-2-indolinone 10721 F 83-[(2,4-dimethylpyrrol-5-yl)- methylidenyl]-5-(morpholin-1-yl)-sulfonyl]-2-indolinone 10721 F 9 3-(3-t-butyl-4-hydroxybenzylidenyl)-5-(morpholin-1-yl)sulfonyl]-2- indolinone 10721 F 10 3-(3-bromo-5-t-butyl-4-hydroxy- benzylidenyl)-5-(morpholin-1-yl)-sulfonyl]-2-indolinone 10721 F 11  3-(3,5-di-t-butyl-4-hydroxybenzyl-idenyl)-5-(morpholin-1-yl)- sulfonyl]-2-indolinone 10721 G 23[(1-methylbenzimidazol-2-yl)- methylidenyl]-5-(2-chloroethyl)-2-indolinone 10721 G 3 3-[(4-chloro-1-methylpyrazol-3-yl)methylidenyl]-5-(2-chloro- ethyl)-2-indolinone 10721 G 43-[(2,3-dimethylthien-5-yl)- methylidenyl]-5-(2-chloroethyl)-2-indolinone 10721 G 5 3-[(4.5,6,7-tetrahydroindol-2-yl)-methylidenyl]-5-(2-chloroethyl)- 2-indolinone 10721 G 63-(3-chloromethyl-2-hydroxy-5- nitrobenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10721 G 7 3-[(2-chlorothien-5-yl)methyl-idenyl]-5-(2-chloroethyl)- 2-indolinone 10721 G 83-[(2,4-dimethylpyrrol-5-yl)- methylidenyl)-5-(2-chloroethyl)-2-indolinone 10721 G 9 3-(3-t-butyl-4-hydroxybenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10721 G 10 3-(3-bromo-5-t-butyl-4-hydroxy- benzylidenyl)-5-(2-chloroethyl)-2-indolinone 10721 G 11  3-(3,5-di-t-butyl-4-hydroxybenzyl-idenyl)-5-(2-chloroethyl)-2- indolinone 10722 A 23-(3-t-butyl-4-hydroxy-5-nitro- benzylidenyl)-5,7-dibromo-2- indolinone10722 A 3 3-(2,4,6-trihydroxybenzylidenyl)- 5,7-dibromo-2-indolinone10722 A 4 3-[(2-nitrothien-5-yl)methyl- idenyl]-5,7-dibromo-2-indolinone10722 A 5 3-(4-carboxybenzylidenyl)-5,7- dibromo-2-indolinone 10722 A 63-(2,4-difluorobenzylidenyl)-5,7- dibromo-2-indolinone 10722 A 73-(3,5-dimethyl-4-hydroxybenzyl- idenyl)-5,7-dibromo-2-indolinone 10722A 8 3-(3-t-butyl-5-chloro-4-hydroxy- benzylidenyl)-5,7-dibromo-2-indolinone 10722 A 9 3-[(2-nitrothien-4-yl)methyl-idenyl]-5,7-dibromo-2-indolinone 10722 A 10 3-(4-di-n-butylaminobenzylidenyl)- 5,7-dibromo-2-indolinone 10722 A 11 3-[4-(trifluoromethyl)benzyl- idenyl]-5,7-dibromo-2-indolinone 10722 B 23-(3-t-butyl-4-hydroxy-5-nitro- benzylidenyl)-5-iodo-2-indolinone 10722B 3 3-(2,4,6-trihydroxybenzylidenyl)- 5-iodo-2-indolinone 10722 B 43-[(2-nitrothien-5-yl)methyl- idenyl-5-iodo-2-indolinone 10722 B 53-(4-carboxybenzylidenyl)-5- iodo-2-indolinone 10722 B 63-(2,4-difluorobenzylidenyl)- 5-iodo-2-indolinone 10722 B 73-(3,5-dimethyl-4-hydroxybenzyl- idenyl)-5-iodo-2-indolinone 10722 B 83-(3-t-butyl-5-chloro-4-hydroxy- benzylidenyl)-5-iodo-2-indolinone 10722B 9 3-[(2-nitrothien-4-yl)methyl- idenyl]-5-iodo-2-indolinone 10722 B10  3-(4-di-n-butylaminobenzylidenyl)- 5-iodo-2-indolinone 10722 B 11 3-(4-(trifluoromethyl)benzylidenyl)- 5-iodo-2-indolinone 10722 C 23-(3-t-butyl-4-hydroxy-5-nitro- benzylidenyl)-5-dibromo-4-methyl-2-indolinone 10722 C 3 3-(2,4,6-trihydroxybenzylidenyl)-5-dibromo-4-methyl-2-indolinone 10722 C 4 3-[(2-nitrothien-5-yl)methyl-idenyl]-5-dibromo-4-methyl- 2-indolinone 10722 C 53-(4-carboxybenzylidenyl)-5- dibromo-4-methyl-2-indolinone 10722 C 63-(2,4-difluorobenzylidenyl)- 5-dibromo-4-methyl-2-indolinone 10722 C 73-(3,5-dimethyl-4-hydroxybenzyl- idenyl)-5-dibromo-4-methyl-2-indolinone 10722 C 8 3-(3-t-butyl-5-chloro-4-hydroxy-benzylidenyl)-5-dibromo-4-methyl- 2-indolinone 10722 C 93-[(2-nitrothien-4-yl)methyl- idenyl]-5-dibromo-4-methyl- 2-indolinone10722 C 10  3-(4-di-n-butylaminobenzylidenyl)-5-dibromo-4-methyl-2-indolinone 10722 C 11 3-[4-(trifluoromethyl)benzyl- idenyl]-5-dibromo-4-methyl-2- indolinone10722 D 2 3-(3-t-butyl-4-hydroxy-5-nitro- benzylidenyl)-5-methylamino-sulfonyl-2-indolinone 10722 D 3 3-(2,4,6-trihydroxybenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10722 D 4 3-[(2-nitrothien-5-yl)methyl-idenyl]-5-methylaminosulfonyl- 2-indolinone 10722 D 53-(4-carboxybenzylidenyl)-5-methyl- aminosulfonyl-2-indolinone 10722 D 63-(2,4-difluorobenzylidenyl)-5- methylaminosulfonyl-2-indolinone 10722 D7 3-(3,5-dimethyl-4-hydroxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10722 D 8 3-(3-t-butyl-5-chloro-4-hydroxy-benzylidenyl)-5-methylamino- sulfonyl-2-indolinone 10722 D 93-[(2-nitrothien-4-yl)methyl- idenyl]-5-methylamino-sulfonyl-2-indolinone 10722 D 10  3-(4-di-n-butylaminobenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10722 D 11 3-[4-(trifluoromethyl)benzyl- idenyl]-5-methylamino-sulfonyl-2-indolinone 10722 E 2 3-(3-t-butyl-4-hydroxy-5-nitro-benzylidenyl)-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10722 E 3 3-(2,4,6-trihydroxybenzylidenyl)-5-[4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10722 E 43-[(2-nitrothien-5-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10722 E 53-(4-carboxybenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10722 E 6 3-(2,4-difluorobenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10722 E 73-(3,5-dimethyl-4-hydroxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10722 E 83-(3-t-butyl-5-chloro-4-hydroxy- benzylidenyl)-5-[4-(trifluoro-methyl)phenylaminosulfonyl]-2- indolinone 10722 E 93-[(2-nitrothien-4-yl)methyl- idenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10722 E 10 3-(4-di-n-butylaminobenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10722 E 11  3-[4-(trifluoromethyl)benzyl-idenyl]-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone 10722F 2 3-(3-t-butyl-4-hydroxy-5-nitro- benzylidenyl)-5-(morpholin-1-yl)-aminosulfonyl-2-indolinone 10722 F 3 3-(2,4,6-trihydroxybenzylidenyl)-5-(morpholin-1-yl)aminosulfonyl- 2-indolinone 10722 F 43-[(2-nitrothien-5-yl)methyl- idenyl]-5-(morpholin-1-yl)aminosulfonyl-2-indolinone 10722 F 5 3-(4-carboxybenzylidenyl)-5-(morpholin-1-yl)aminosulfonyl- 2-indolinone 10722 F 63-(2,4-difluorobenzylidenyl)- 5-(morpholin-1-yl)aminosulfonyl-2-indolinone 10722 F 7 3-(3,5-dimethyl-4-hydroxybenzyl-idenyl)-5-(morpholin-1-yl)amino- sulfonyl-2-indolinone 10722 F 83-(3-t-butyl-5-chloro-4-hydroxy- benzylidenyl)-5-(morpholin-1-yl)-aminosulfonyl-2-indolinone 10722 F 9 3[(2-nitrothien-4-yl)methyl-idenyl]-5-(morpholin-1-yl)- aminosulfonyl-2-indolinone 10722 F 10 3-(4-di-n-butylaminobenzylidenyl)- 5-(morpholin-1-yl)aminosulfonyl-2-indolinone 10722 F 11  3-[4-(trifluoromethyl)benzyl-idenyl[-5-(morpholin-1-yl)amino- sulfonyl-2-indolinone 10722 G 23-(3-t-butyl-4-hydroxy-5-nitro- benzylidenyl)-5-(2-chloroethyl)-2-indolinone 10722 G 3 3-(2,4,6-trihydroxybenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10722 G 4 3-[(2-nitrothien-5-yl)methyl-idenyl]-5-(2-chloroethyl-2- indolinone 10722 G 53-(4-carboxybenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10722 G 63-(2,4-difluorobenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10722 G 73-(3,5-dimethyl-4-hydroxybenzyl- idenyl)-5-(2-chloroethyl)-2- indolinone10722 G 8 3-(3-t-butyl-5-chloro-4-hydroxy-benzylidenyl)-5-(2-chloroethyl)-2- indolinone 10722 G 93-[(2-nitrothien-4-yl)methyl- idenyl]-5-(2-chloroethyl)-2- indolinone10722 G 10  3-(4-di-n-butylaminobenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10722 G 11  3-[4-(trifluoromethyl)benzyl-idenyl]-5-(2-chloroethyl)-2- indolinone 10723 A 23-(2,3,4-trihydroxybenzylidenyl)- 5,7-dibromo-2-indolinone 10723 A 33-(2-hydroxy-3-methoxybenzyl- idenyl)-5,7-dibromo-2-indolinone 10723 A 43-(3-bromo-4,5-dihydroxybenzyl- idenyl)-5,7-dibromo-2-indolinone 10723 A5 3-(3,4-diacetoxybenzylidenyl)- 5,7-dibromo-2-indolinone 10723 A 63-(4-hydroxy-3-methylbenzylidenyl)- 5,7-dibromo-2-indolinone 10723 A 73-(2-bromobenzylidenyl)-5,7- dibromo-2-indolinone 10723 A 83-(2,4-dihydroxybenzylidenyl)- 5,7-dibromo-2-indolinone 10723 A 93-(2-hydroxy-4-methoxybenzyl- idenyl)-5,7-dibromo-2-indolinone 10723 A10  3-(3-bromobenzylidenyl)-5,7- dibromo-2-indolinone 10723 A 11 3-(3,5-di-t-butyl-2-hydroxybenzyl- idenyl)-5,7-dibromo-2-indolinone10723 B 2 3-(2,3,4-trihydroxybenzylidenyl)- 5-iodo-2-indolinone 10723 B3 3-(2-hydroxy-3-methoxybenzyl- idenyl)-5-iodo-2-indolinone 10723 B 43-(3-bromo-4,5-dihydroxybenzyl- idenyl)-5-iodo-2-indolinone 10723 B 53-(3,4-diacetoxybenzylidenyl)- 5-iodo-2-indolinone 10723 B 63-(4-hydroxy-3-methylbenzyl- idenyl)-5-iodo-2-indolinone 10723 B 73-(2-bromobenzylidenyl)-5-iodo- 2-indolinone 10723 B 83-(2,4-dihydroxybenzylidenyl)-5- iodo-2-indolinone 10723 B 93-(2-hydroxy-4-methoxybenzyl- idenyl)-5-iodo-2-indolinone 10723 B 10 3-(3-bromobenzylidenyl)-5-iodo- 2-indolinone 10723 B 11 3-(3,5-di-t-butyl-2-hydroxybenzyl- idenyl)-5-iodo-2-indolinone 10723 C 23-(2,3,4-trihydroxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10723 C3 3-(2-hydroxy-3-methoxybenzyl- idenyl)-5-bromo-4-methyl-2- indolinone10723 C 4 3-(3-bromo-4,5-dihydroxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10723 C 5 3-(3,4-diacetoxybenzylidenyl)-5-bromo-4-methyl-2-indolinone 10723 C 6 3-(4-hydroxy-3-methylbenzyl-idenyl)-5-bromo-4-methyl-2- indolinone 10723 C 73-(2-bromobenzylidenyl)-5-bromo- 4-methyl-2-indolinone 10723 C 83-(2,4-dihydroxybenzylidenyl)-5- bromo-4-methyl-2-indolinone 10723 C 93-(2-hydroxy-4-methoxybenzyl- idenyl-5-bromo-4-methyl-2- indolinone10723 C 10  3-(3-bromobenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10723C 11  3-(3,5-di-t-butyl-2-hydroxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10723 D 2 3-(2,3,4-trihydroxybenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10723 D 3 3-(2-hydroxy-3-methoxybenzyl-idenyl-5-methylaminosulfonyl- 2-indolinone 10723 D 43-(3-bromo-4,5-dihydroxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10723 D 5 3-(3,4-diacetoxybenzylidenyl)-5-methylaminosulfonyl-2- indolinone 10723 D 63-(4-hydroxy-3-methylbenzyl- idenyl)-5-methylaminosulfonyl- 2-indolinone10723 D 7 3-(2-bromobenzylidenyl)-5-methyl- aminosulfonyl-2-indolinone10723 D 8 3-(2,4-dihydroxybenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10723 D 9 3-(2-hydroxy-4-methoxybenzylidenyl)-5-methylaminosulfonyl- 2-indolinone 10723 D 10 3-(3-bromobenzylidenyl)-5-methyl- aminosulfonyl-2-indolinone 10723 D 11 3-(3,5-di-t-butyl-2-hydroxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10723 E 2 3-(2,3,4-trihydroxybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10723 E 33-(2-hydroxy-3-methoxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2- indolinone 10723 E 43-(3-bromo-4,5-dihydroxybenzyl- idenyl)-5-[4-(trifluoromethy)-phenylaminosulfonyl-2-indolinone 10723 E 53-(3,4-diacetoxybenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10723 E 6 3-(4-hydroxy-3-methylbenzylidenyl)-5-[4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10723 E 73-(2-bromobenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10723 E 8 3-(2,4-dihydroxybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10723 E 93-(2-hydroxy-4-methoxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10723 E 10 3-(3-bromobenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10723 E 11  3-(3,5-di-t-butyl-2-hydroxybenzyl-idenyl)-5-[4-(trifluoromethyl)- phenylaminosulfonyl-2-indolinone 10723 F2 3-(2,3,4-trihydroxybenzylidenyl)- 5-(morpholin-1-yl)aminosulfonyl-2-indolinone 10723 F 3 3-(2-hydroxy-3-methoxybenzyl-idenyl)-5-(morpholin-1-yl)amino- sulfonyl-2-indolinone 10723 F 43-(3-bromo-4,5-dihydroxybenzyl- idenyl)-5-(morpholin-1-yl)amino-sulfonyl-2-indolinone 10723 F 5 3-(3,4-diacetoxybenzylidenyl)-5-(morpholin-1-yl)amino- sulfonyl-2-indolinone 10723 F 63-(4-hydroxy-3-methylbenzylidenyl)- 5-(morpholin-1-yl)aminosulfonyl-2-indolinone 10723 F 7 3-(2-bromobenzylidenyl)-5-(morpholin-1-yl)aminosulfonyl- 2-indolinone 10723 F 83-(2,4-dihydroxybenzylidenyl)-5- (morpholin-1-yl)aminosulfonyl-2-indolinone 10723 F 9 3-(2-hydroxy-4-methoxybenzyl-idenyl)-5-(morpholin-1-yl)amino- sulfonyl-2-indolinone 10723 F 10 3-(3-bromobenzylidenyl)-5- (morpholin-1-yl)aminosulfonyl- 2-indolinone10723 F 11  3-(3,5-di-t-butyl-2-hydroxybenzyl-idenyl)5-(morpholin-1-yl)amino- sulfonyl-2-indolinone 10723 G 23-(2,3,4-trihydroxybenzylidenyl)- 5-(2-chloroethyl)2-indolinone 10723 G3 3-(2-hydroxy-3-methoxybenzyl- idenyl)-5-(2-chloroethyl)-2- indolinone10723 G 4 3-(3-bromo-4,5-dihydroxybenzyl- idenyl)-5-(2-chloroethyl)-2-indolinone 10723 G 5 3-(3,4-diacetoxybenzyhdenyl)-5-(2-chloroethyl)-2-indolinone 10723 G 6 3-(4-hydroxy-3-methylbenzyl-idenyl)-5-(2-chloroethyl)-2- indolinone 10723 G 73-(2-bromobenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10723 G 83-(2,4-dihydroxybenzylidenyl)- 5-(2-chloroethyl)-2-indolinone 10723 G 93-(2-hydroxy-4-methoxybenzyl- idenyl)-5-(2-chloroethyl)-2- indolinone10723 G 10  3-(3-bromobenzylidenyl)-5-(2- chloroethyl)-2-indolinone10723 G 11  3-(3,5-di-t-butyl-2-hydroxybenzyl-idenyl)-5-(2-chloroethyl)-2- indolinone 10724 A 23-[(1-dimethylaminonapth-4-yl)- methylidenyl]-5,7-dibromo-2- indolinone10724 A 3 3-(4-hydroxy-3-nitrobenzylidenyl)- 5,7-dibromo-2-indolinone10724 A 4 3-(3-hydroxy-4-nitrobenzylidenyl)- 5,7-dibromo-2-indolinone10724 A 5 3[(8-hydroxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizin-9-yl)- methylidenyl]-5,7-dibromo-2- indolinone10724 A 6 3-(3,5-diisopropyl-4-hydroxybenzyl-idenyl)-5,7-dibromo-2-indolinone 10724 A 7 3-[(benzo[b]furan-2-yl)-methylidenyl]-5,7-dibromo-2- indolinone 10724 A 93-[[1-(4-chlorophenyl)pyrrol- 2-yl]methylidenyl]-5,7-dibromo-2-indolinone 10724 A 10  3-[(2-ethylfuran-5-yl)methyl-idenyl]-5,7-dibromo-2-indolinone 10724 A 11 3-[(3,4-dimethylthieno[2,3-b] thien-2-yl)methylidenyl]-5,7-dibromo-2-indolinone 10724 B 2 3-[(1-dimethylaminonapth-4-yl)-methylidenyl]-5-iodo-2- indolinone 10724 B 33-(4-hydroxy-3-nitrobenzylidenyl)- 5-iodo-2-indolinone 10724 B 43-(3-hydroxy-4-nitrobenzylidenyl)- 5-iodo-2-indolinone 10724 B 53-[(8-hydroxy-2,3,6,7-tetrahydro- 1H,5H-benzo[ij]quinolizin-9-yl)-methylidenyl]-5-iodo-2-indolinone 10724 B 63-(3,5-diisopropyl-4-hydroxybenzyl- idenyl)-5-iodo-2-indolinone 10724 B7 3-[(benzo[b]furan-2-yl)methyl- idenyl]-5-iodo-2-indolinone 10724 B 93-[[1-(4-chlorophenyl)pyrrol- 2-yl]methylidenyl]-5-iodo-2- indolinone10724 B 10  3-[(2-ethylfuran-5-yl)methyl- idenyl]-5-iodo-2-indolinone10724 B 11  3-[(3,4-dimethylthieno[2,3-b]thien-2-yl)methylidenyl]-5-iodo-2- indolinone 10724 C 23-[(1-dimethylaminonapth-4-yl)- methylidenyl]-5-bromo-4-methyl-2-indolinone 10724 C 3 3-(4-hydroxy-3-nitrobenzylidenyl)-5-bromo-4-methyl-2-indolinone 10724 C 43-(3-hydroxy-4-nitrobenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10724 C5 3-[(8-hydroxy-2,3,6,7-tetrahydro- 1H,5H-benzo[ij]quinolizin-9-yl)-methylidenyl]-5-bromo-4-methyl- 2-indolinone 10724 C 63-(3,5-diisopropyl-4-hydroxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10724 C 7 3-[(benzo[b]furan-2-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10724 C 93-[[[1-(4-chlorophenyl)pyrrol-2- yl]methylidenyl]-5-bromo-4-methyl-2-indolinone 10724 C 10  3-[(2-ethylfuran-5-yl)methyl-idenyl]-5-bromo-methyl-2- indolinone 10724 C 11 3-[(3,4-dimethylthieno[2,3-b]thien- 2-yl)methylidenyl]-5-bromo-4-methyl-2-indolinone 10724 D 2 3-[(1-dimethylaminonapth-4-yl)-methylidenyl]-5-methylamino- sulfonyl-2-indolinone 10724 D 33-(4-hydroxy-3-nitrobenzylidenyl)- 5-methylaminosulfonyl-2-indolinone10724 D 4 3-(3-hydroxy-4-nitrobenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10724 D 53-[(8-hydroxy-2,3,6,7-tetrahydro- 1H,5H-bemzp[ij]quinolizin-9-yl)methylidenyl]-5-methylamino- sulfonyl-2-indolinone 10724 D 63-(3,5-diisopropyl-4-hydroxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10724 D 7 3-[(benzo[b]furan-2-yl)methylidenyl]-5-methylaminosulfonyl- 2-indolinone 10724 D 93-[1-(4-chlorophenyl)pyrrol-2-yl] methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10724 D 10  3-[(2-ethylfuran-5-yl)methyl-idenyl]-5-methylaminosulfonyl- 2-indolinone 10724 D 11 3-[(3,4-dimethylthieno[2,3-b]thien- 2-yl)methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10724 E 3 3-[(1-dimethylaminonapth-4-yl)-methylidenyl]-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10724 E 3 3-(4-hydroxy-3-nitrobenzyl- idenyl)-5-(4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10724 E 43-(3-hydroxy-4-nitrobenzylidenyl)-5- [4-(trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10724 E 5 3-[(8-hydroxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizin-9-yl) methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10724 E 63-(3,5-diisopropyl-4-hydroxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfanyl]-2-indolinone 10724 E 73-[(benzo[b]furan-2-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10724 E 93-[1-(4-chlorophenyl)pyrrol-2-yl]- methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl- 2-indolinone 10724 E 10 3-[(2-ethylfuran-5-yl)methyl- idenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10724 E 11 3-[(3,4-dimethylthieno[2,3-b]thien- 2-yl)methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10724 F 23-[(1-dimethylaminonapth-4-yl)- methylidenyl]-5-(morpholin-1-yl)-aminosulfonyl-2-indolinone 10724 F 3 3-(4-hydroxy-3-nitrobenzylidenyl)-5-(morpholin-1-yl)aminosulfonyl- 2-indolinone 10724 F 43-(3-hydroxy-4-nitrobenzylidenyl)- 5-(morpholin-1-yl)aminosulfonyl-2-indolinone 10724 F 5 3-[(8-hydroxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizin-9-yl)- methylidenyl]-5-(morpholin-1-yl)-aminosulfonyl-2-indolinone 10724 F 6 3-(3,5-diisopropyl-4-hydroxybenzyl-idenyl)-5-(morpholin-1-yl)amino- sulfonyl-2-indolinone 10724 F 73-[(benzo[b]furan-2-yl)methyl- idenyl]-5-(morpholin-1-yl)amino-sulfonyl-2-indolinone 10724 F 9 3-[[1-(4-chlorophenyl)pyrrol-2-yl]-methylidenyl]-5-(morpholin-1-yl)- aminosulfonyl-2-indolinone 10724 F 10 3-[(2-ethylfuran-5-yl)methyl- idenyi]-5-(morpholin-1-yl)amino-sulfonyl-2-indolinone 10724 F 11  3-[(3,4-dimethylthieno[2,3-b]thien-2-yl)methylidenyl]-5-(morpholin-1-yl)- aminosulfonyl-2-indolinone 10724G 2 3-[(1-dimethylaminanapth-4-yl)- methylidenyl]-5-(2-chloroethyl)-2-indolinone 10724 G 3 3-(4-hydroxy-3-nitrobenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10724 G 43-(3-hydroxy-4-nitrobenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10724G 5 3-[(8-hydroxy-2,3,6,7-tetrahydro- 1H,5H-bemzp[ij]quinolizin-9-yl)-methylidenyl]-5-(2-chloroethyl)- 2-indolinone 10724 G 63-(3,5-diisopropyl-4-hydroxybenzyl- idenyl)-5-(2-chloroethyl)-2-indolinone 10724 G 7 3-[(benzo[b]furan-2-yl)methyl-idenyl]-5-(2-chloroethyl)-2- indolinone 10724 G 93-[[(1-(4-chlorophenyl)pyrrol-2-yl]- methylidenyl]-5-(2-chloroethyl)-2-indolinone 10724 G 10  3-[(2-ethylfuran-5-yl)methyl-idenyl]-5-(2-chloroethyl)-2- indolinone 10724 G 11 3-[(3,4-dimethylthieno[+2,3-b]thien-2-yl)methylidenyl]-5-(2-chloroethyl)- 2-indolinone 10725 A 23-[(3-bromothien-2-yl)methyl- idenyl]-5,7-dibromo-2-indolinone 10725 A 33-(2-bromo-6-hydroxy-5-methoxybenzyl- idenyl)-5,7-dibromo-2-indolinone10725 A 4 3-[(2-methylfuran-5-yl)methyl-idenyl]-5,7-dibromo-2-indolinone 10725 A 53-[(3-methylpyrazol-5-yl)methyl- idenyl]-5,7-dibromo-2-indolinone 10725A 6 3-(2-hydroxy-6-methoxy-4-methyl- benzylidenyl)-5,7-dibromo-2-indolinone 10725 A 7 3-[4-(4-formylpiperazin-1-yl)benzyl-idenyl]-5,7-dibromo-2-indolinone 10725 A 83-[4-(morpholin-1-yl)benzylidenyl]- 5,7-dibromo-2-indolinone 10725 A 93-[[2-chloro-4-methoxycarbonyl- 3-(methoxycarbonylmethyl)pyrrol-5-yl]methylidenyl]-5,7- dibromo-4-methyl-2-indolinone 10725 A 10 3-[[4-bromo-2-(4-chlorophenyl)- pyrazol-3-yl)methylidenyl]-5,7-dibromo-4-methyl-2-indolinone 10725 A 11 3-[(imidazol-4-yl)methylidenyl]- 5,7-dibromo-4-methyl-2-indolinone 10725B 2 3-[(3-bromothien-2-yl)methyl- idenyl]-5-iodo-2-indolinone 10725 B 33-(2-bromo-6-hydroxy-5-methoxy- benzylidenyl)-5-iodo-2-indolinone 10725B 4 3-[(2-methylfuran-5-yl)methyl- idenyi]-5-iodo-2-indolinone 10725 B 53-[(3-methylpyrazol-5-yl)methyl- idenyl]-5-iodo-2-indolinone 10725 B 63-(2-hydroxy-5-methoxy-4-methyl- benzylidenyl)-5-iodo-2-indolinone 10725B 7 3-[4-(4-formylpiperazin-1-yl)- benzylidenyl]-5-iodo-2- indolinone10725 B 8 3-[4-(morpholin-1-yl)benzyl- idenyi]-5-iodo-2-indolinone 10725B 9 3-[[2-chloro-4-methoxycarbonyl- 3-(methoxycarbonylmethyl)Pyrrol-5-yl]methylidenyl]-5-iodo-2- indolinone 10725 B 10 3-[[4-bromo-2-(4-chlorophenyl)- pyrazol-3-yl]methylidenyl]-5-iodo-2-indolinone 10725 B 11  3-[(imidazol-4-yl)methylidenyl]-5-iodo-2-indolinone 10725 C 2 3-[(3-bromothien-2-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10725 C 33-(2-bromo-6-hydroxy-5-methoxy- benzylidenyl)-5-bromo-4-methyl-2-indolinone 10725 C 4 3-[(2-methylfuran-5-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10725 C 53-[(3-methylpyrazol-5-yl)methyl- idenyl]-5-bromo-4-methyl-2- indolinone10725 C 6 3-(2-hydroxy-6-methoxy-4-methyl-benzylidenyl)-5-bromo-4-methyl- 2-indolinone 10725 C 73-[(4-(4-formylpiperazin-1-yl)benyl- idenyl]-5-bromo-4-methyl-2-indolinone 10725 C 8 3-[4-(morpholin-1-yl)benzyl-idenyl]-5-bromo-4-methyl-2- indolinone 10725 C 93-[[2-chloro-4-methoxycarbonyl- 3-(methoxycarbonylmethyl)pyrrol-5-yl]methylidenyl]-5-bromo-4- methyl-2-indolinone 10725 C 10 3-[[4-bromo-2-(4-chlorophenyl)pyrazol- 3-yl]methylidenyl]-5-bromo-4-methyl-2-indolinone 10725 C 11  3-[(imidazol-4-yl)methylidenyl]-5-bromo-4-methyl-2-indolinone 10725 D 2 3-[(3-bromothien-2-yl)methyl-idenyl]-5-methylaminosulfonyl- 2-indolinone 10725 D 33-(2-bromo-6-hydroxy-5-methoxy- benzylidenyl)-5-methylamino-sulfonyl-2-indolinone 10725 D 4 3-[(2-methylfuran-5-yl)methyl-idenyl]-5-methylaminosulfonyl- 2-indolinone 10725 D 53-[(3-methylpyrazol-5-yl)methyl- idenyl]-5-methylaminosulfonly-2-indolinone 10725 D 6 3-(2-hydroxy-6-methoxy-4-methyl-benzylidenyl)-5-methylamino- sulfonyl-2-indolinone 10725 D 73-[4-(4-formylpiperazin-1-yl)- benzylidenyl]-5-methylamino-sulfonyl-2-indolinone 10725 D 8 3-[4-(morpholin-1-yl)benzyl-idenyl]-5-methylamino- sulfonyl-2-indolinone 10725 D 93-[[2-chloro-4-methoxy- carbonyl-3-(methoxycarbonyl-methyl)pyrrol-5-yl]methyl- idenyl]-5-methylamino- sulfonyl-2-indolinone10725 D 10  3-[[4-bromo-2-(4-chloro- phenyl)pyrazol-3-yl]methyl-idenyl]-5-methylamino- sulfonyl-2-indolinone 10725 D 11 3-[(imidazol-4-yl)methyl- idenyl]-5-methylamino- sulfonyl-2-indolinone10725 E 2 3-[(3-bromothien-2-yl)methyl- idenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10725 E 33-(2-bromo-6-hydroxy-5-methoxy- benzylidenyl)-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10725 E 43-[(2-methylfuran-5-yl)methyl- idenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10725 E 53-[(3-methylpyrazol-5-yl)- methylidenyl]-5-[4-(tri-fluoromethyl)phenylamino- sulfonyl-2-indolinone 10725 E 63-(2-hydroxy-6-methoxy-4- methybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10725 E 73-[4-(4-formylpiperazin-1-yl)- benzylidenyl]-5-[4-(tri-fluoromethyl)phenylamino- sulfonyl]-2-indolinone 10725 E 83-[4-(morpholin-1-yl)benzyl- idenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10725 E 93-[[2-chloro-4-methoxy- carbonyl-3-(methoxy- carbonylmethyl)pyrro-5-yl-methylidenyl)-5-[4-(tri- fluoromethyl)phenylamino- sulfonyl-2-indolinone10725 E 10  3-[[4-bromo-2-(4-chlorophenyl) pyrazol-3-yl]methylidenyl]-5-[4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10725 E 11 3-[(imidazol-4-yl)methylidenyl]- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10725 F 2 3-[(3-bromothien-2-yl)methyl-idenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10725 F 33-(2-bromo-6-hydroxy-5-methoxy- benzylidenyl)-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10725 F 4 3-[(2-methylfuran-5-yl)methyl-idenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10725 F 53[(3-methylpyrazol-5-yl)methyl- idenyl]-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10725 F 6 3-(2-hydroxy-6-methoxy-4-methyl-benzylidenyl)-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10725 F 73-[4-(4-formylpiperazin-1-yl)- benzylidenyl]-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10725 F 8 3-[4-(morpholin-1-yl)benzyl-idenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10725 F 93-[[2-chloro-4-methoxy- carbonyl-3-(methoxycarbonyl-methyl)pyrrol-5-yl]methylidenyl]- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10725 F 10  3-[[4-bromo-2-(4-chlorophenyl)-pyrazol-3-yl]methylidenyl]-5- (morpholin-1-yl)sulfonyl-2- indolinone10725 F 11  3-[(imidazol-4-yl)methylidenyl]-5-(morpholin-1-yl)sulfonyl-2- indolinone 10725 G 23-[(3-bromothien-2-yl)methyl- idenyl]-5-(2-chloroethyl)-2- indolinone10725 G 3 3-(2-bromo-6-hydroxy-5-methoxy-benzylidenyl)-5-(2-chloroethyl)- 2-indolinone 10725 G 43-[(2-methylfuran-5-yl)methyl- ideny]-5-(2-chloroethyl)-2- indolinone10725 G 5 3-[(3-methylpyrazol-5-yl)- methylidenyl]-5-(2-chloroethyl)-2-indolinone 10725 G 6 3-(2-hydro-6-methoxy-4-methyl-benzylidenyl)-5-(2-chloroethyl)- 2-indolinone 10725 G 73-[4-(4-formylpiperazin-1-yl)- benzylidenyl]-5-(2-chloroethyl)-2-indolinone 10725 G 8 3-[4-(morpholin-1-yl)benzyl-idenyl]-5-(2-chloroethyl)- 2-indolinone 10725 G 93-[[2-chloro-4-methoxy- carbonyl-3-(methoxycarbonyl-methyl)pyrrol-5-yl]methyl- idenyl]-5-(2-chloroethyl)- 2-indolinone 10725G 10  3-[[4-bromo-2-(4-chlorophenyl)- pyrazol-3-yl]methylidenyl]-5-(2-chloroethyl)-2-indolinone 10725 G 11 3-[(imidazol-4-yl)methylidenyl]- 5-(2-chloroethyl)-2-indolinone 10726 A3 3-[(2-ethoxycarbonyl-4-methoxy- carbonyl-3-methylpyrrol-5-yl)-methylidenyl]-5,7-dibromo-2- indolinone 10726 A 43-(3-t-butyl-4-hydroxy-5-methyl- benzylidenyl)-5,7-dibromo-2- indolinone10726 A 5 3-[(2-bromofuran-5-yl)methyl- idenyl]-5,7-dibromo-2-indolinone 10726 A 6 3-[(1,3-dimethylpyrrol-4-yl)methyl-idenyl]-5,7-dibromo-2-indolinone 10726 A 7 3-[(5,8-dihydroxy-1,2,3,4-tetrahydronapth-6-yl)methyl- idenyl]-5,7-dibromo-2- indolinone 10726 A 83-(5-fluoro-2-oxindol-3-idenyl)- 5,7-dibromo-2-indolinone 10726 A 93-(2-oxindol-3-idenyl)-5,7- dibromo-2-indolinone 10726 A 10 3-[(2-ethylthien-5-yl)methyl- idenyl]-5,7-dibromo-2- indolinone 10726 A11  3-(4-methoxybenzylidenyl)-5,7- dibromo-2-indolinone 10726 B 33-[(2-ethoxycarbonyl-4-methoxy- carbonyl-3-methylpyrrol-5-yl)-methylidenyl]-5-iodo-2- indolinone 10726 B 43-(3-t-butyl-4-hydroxy-5-methyl- benzylidenyl)-5-iodo-2-indolinone 10726B 5 3-[(2-bromofuran-5-yl)methyl- idenyl]-5-iodo-2-indolinone 10726 B 63-[(1,3-dimethylpyrrol-4-yl)- methylidenyl]-5-iodo-2- indolinone 10726 B7 3-[(5,8-dihydroxy-1,2,3,4-tetra- hydronapth-6-yl)methylidenyl)-5-iodo-2-indolinone 10726 B 8 3-(5-fluoro-2-oxindol-3-idenyl)-5-iodo-2-indolinone 10726 B 9 3-[(2-oxindol-3-idenyl)methyl-idenyl]-5-iodo-2-indolinone 10726 B 10  3-[(2-ethylthien-5-yl)methyl-idenyl)-5-iodo-2-indolinone 10726 B 11  3-(4-methoxybenzylidenyl)-5-iodo-2-indolinone 10726 C 3 3-[(2-ethoxycarbonyl-4-methoxy-carbonyl-3-methylpyrrol-5-yl)- methylideny]l-5-bromo-4-methyl-2-indolinone 10726 C 4 3-(3-t-butyl-4-hydroxy-5-methyl-benzylidenyl)-5-bromo-4-methyl- 2-indolinone 10726 C 53-[(2-bromofuran-5-yl)methyl- idenyl]-5-bromo-4-methyl-2- indolinone10726 C 6 3-[(1,3-dimethylpyrrol-4-yl)- methylidenyi]-5-bromo-4-methyl-2-indolinone 10726 C 7 3-[(5,8-dihydroxy-1,2,3,4-tetra-hydronapth-6-yl)methylidenyl]- 5-bromo-4-methyl-2-indolinone 10726 C 83-(5-fluoro-2-oxindol-3-idenyl)- 5-bromo-4-methyl-2-indolinone 10726 C 93-(2-oxindol-3-idenyl)-5-bromo- 4-methyl-2-indolinone 10726 C 10 3-[(2-ethylthien-5-yl)methyl- idenyl]-5-bromo-4-methyl-2- indolinone10726 C 11  3-(4-methoxybenzylidenyl)-5-bromo- 4-methyl-2-indolinone10726 D 3 3-[(2-ethoxycarbonyl-4-methoxy-carbonyl-3-methylpyrrol-5-yl)methyl- idenyI]-5-methylaminosulfonyl-2-indolinone 10726 D 4 3-(3-t-butyl-4-hydroxy-5-methyl-benzylidenyl)-5-methylamino- sulfonyl-2-indolinone 10726 D 53-[(2-bromofuran-5-yl)methyl- idenyl]-5-methylaminosulfonyl-2-indolinone 10726 D 6 3-[(1,3-dimethylpyrrol-4-yl)-methylidenyl]-5-methylamino- sulfonyl-2-indolinone 10726 D 73-[(5,8-dihydroxy-1,2,3,4-tetra- hydronapth-6-yl)methylidenyl]-5-methylaminosulfonyl-2-indolinone 10726 D 83-(5-fluoro-2-oxindol-3-idenyl)- 5-methylaminosulfonyl-2- indolinone10726 D 9 3-(2-oxindol-3-idenyl)-5-methyl- aminosulfonyl-2-indolinone10726 D 10  3-[(2-ethylthien-5-yl)methyl- idenyl]-5-methylaminosulfonyl-2-indolinone 10726 D 11  3-(4-methoxybenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10726 E 33-[(2-ethoxycarbonyl-4-methoxy- carbonyl-3-methylpyrrol-5-yl)-methylidenyl]-5-[4-(trifluoro- methyl)phenylaminosulfanyl]- 2-indolinone10726 E 4 3-(3-t-butyl-4-hydroxy-5-methyl-benzylidenyl)-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10726 E 5 3-[(2-bromofuran-5-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl)-2-indolinone 10726 E 63-[(1,3-dimethylpyrrol-4-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10726 E 73-[(5,8-dihydroxy-1,2,3,4-tetra- hydronapth-6-yl)methylidenyl]-5-[4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10726 E 83-(5-fluoro-2-oxindol-3-idenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfanyl]-2-indolinone 10726 E 9 3-(2-oxindol-3-idenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]2-indolinone 10726 E 10 3-[(2-ethylthien-5-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10726 E 11 3-(4-methoxybenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10726 F 3 3-[(2-ethoxycarbonyl-4-methoxy-carbonyl-3-methylpyrrol-5-yl)- methylidenyl]-5-(morpholin-1-yl)sulfonyl-2-indolinone 10726 F 4 3-(3-t-butyl-4-hydroxy-5-methyl-benzylidenyl)-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10726 F 53-[(2-bromofuran-5-yl)methyl- idenyl]-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10726 F 6 3-[(1,3-dimethylpyrrol-4-yl)-methylidenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10726 F 73-[(5,8-dihydroxy-1,2,3,4-tetra- hydronapth-6-yl)methylidenyl]-5-(morpholin-1-yl)sulfonyl-2- indolinone 10726 F 83-(5-fluoro-2-oxindol-3-idenyl)-5- (morpholin-1-yl)sulfonyl-2-indolinone 10726 F 9 3-(2-oxindol-3-idenyl)-5-(morpholin-1-yl)sulfonyl-2-indolinone 10726 F 10  3-[(2-ethylthien-5-yl)methyl-idenyl]-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10726 F 11 3-(4-methoxybenzylidenyl)-5- (morpholin-1-yl)sulfonyl-2- indolinone10726 G 3 3-[(2-ethoxycarbonyl-4-methoxy-carbonyl-3-methylpyrrol-5-yl)methyl- idenyl]-5-(2-chloroethyl)-2-indolinone 10726 G 4 3-(3-t-butyl-4-hydroxy-5-methyl-benzylidenyl)-5-(2-chloroethyl)- 2-indolinone 10726 G 53-[(2-bromofuran-5-yl)methyl- idenyl]-5-(2-chloroethyl)-2- indolinone10726 G 6 3-[(1,3-dimethylpyrrol-4-yl) methylidenyl]-5-(2-chloroethyl)-2-indolinone 10726 G 7 3-[(5,8-dihydroxy-1,2,3,4-teta-hydronapth-6-yl)methylidenyl]-5- (2-chloroethyl)-2-indolinone 10726 G 83-(5-fluoro-2-oxindol-3-idenyl)- 5-(2-chloroethyl)-2-indolinone 10726 G9 3-(2-oxindol-3-idenyl)-5-(2- chloroethyl)-2-indolinone 10726 G 10 3-[(2-ethylthien-5-yl)methyl- idenyl]-5-(2-chloroethyl)- 2-indolinone10726 G 11  3-(4-methoxybenzylidenyl)-5-(2- chloroethyl)-2-indolinone10727 A 2 3-(4-diethyiaminobenzylidenyl)-5,7- dibromo-2-indolinone 10727A 3 3-[(2,4-diethylpyrrol-5-yl)methyl- idenyl]-5,7-dibromo-2-indolinone10727 A 4 3-(3-bromo-5-chloro-2-hydroxy- benzylidenyl)-5,7-dibromo-2-indolinone 10727 A 5 3-[2-(4-chlorophenylmercapto)-benzylidenyl]-5,7-dibromo-2- indolinone 10727 A 63-[(5-chlorobenzodioxolan-6-yl)- methylidenyl]-5,7-dibromo-2- indolinone10727 A 7 3-[(1,4-benzopyranorl-3-yl)methyl-idenyl]-5,7-dibromo-2-indolinone 10727 A 8 3-(3-cyanobenzylidenyl)-5,7-dibromo-2-indolinone 10727 A 9 3-(4-cyanobenzylidenyl)-5,7-dibromo-2-indolinone 10727 A 10  3-(2,5-dihydroybenzylidenyl)-5,7-dibromo-2-indolinone 10727 A 11  3-(2,3-dimethoxybenzylidenyl)-5,7-dibromo-2-indolinone 10727 B 2 3-(4-diethylaminobenzylidenyl)-5-iodo-2-indolinone 10727 B 3 3-[(2,4-diethylpyrrol-5-yl)-methylidenyl]-5-iodo-2- indolinone 10727 B 43-(3-bromo-5-chloro-2-hydroxy- benzylidenyl)-5-iodo-2-indolinone 10727 B5 3-[2-(4-chlorophenylmercapto)- benzylidenyl]-5-iodo-2-indolinone 10727B 6 3-[(5-chlorobenzodioxolan-6-yl)- methyldenyl]-5-iodo-2-indolinone10727 B 7 3-[(1,4-benzopyranon-3-yl)methyl- idenyl]-5-iodo-2-indolinone10727 B 8 3-(3-cyanobenzylidenyl)-5-iodo- 2-indolinone 10727 B 93-(4-cyanobenzylidenyl)-5-iodo- 2-indoiinone 10727 B 10 3-(2,5-dihydroxybenzylidenyl)-5- iodo-2-indolinone 10727 B 11 3-(2,3-dimethoxybenzylidenyl)-5- iodo-2-indolinone 10727 C 23-(4-diethylaminobenzylidenyl)-5- bromo-4-methyl-2-indolinone 10727 C 33-[(2,4-diethylpyrrol-5-yl)methyl- idenyl]-5-bromo-4-methyl-2-indolinone 10727 C 4 3-(3-bromo-5-chloro-2-hydroxybenzyl-idenyl)-5-bromo-4-methyl-2- indolinone 10727 C 53-[2-(4-chlorophenylmercapto)- benzylidenyl]-5-bromo-4-methyl-2-indolinone 10727 C 6 3-[(5-chlorobenzodioxolan-6-yl)-methylidenyl]-5-bromo-4-methyl- 2-indolinone 10727 C 73-[(1,4-benzopyranon-3-yl)methyl- idenyi]-5-bromo-4-methyl-2- indolinone10727 C 8 3-(3-cyanobenzylidenyl)-5-bromo- 4-methyl-2-indolinone 10727 C9 3-(4-cyanobenzylidenyl)-5-bromo- 4-methyl-2-indolinone 10727 C 10 3-(2,5-dihydroybenylidenyl)-5-bromo- 4-methyl-2-indolinone 10727 C 11 3-(2,3-dimethoxybenzylidenyl)-5- bromo-4-methyl-2-indolinone 10727 D 23-(4-diethylaminobenzylidenyl)-5- methylaminosulfonyl-2-indolinone 10727D 3 3-[(2,4-diethylpyrrol-5-yl)- methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10727 D 4 3-(3-bromo-5-chloro-2-hydroxy-benzylidenyl)-5-methylamino- sulfonyl-2-indolinone 10727 D 53-[2-(4-chlorophenylmercapto)- benzylidenyl]-5-methylamino-sulfonyl-2-indolinone 10727 D 6 3-[(5-chlorobenzodioxolan-6-yl)-methylidenyl]-5-methylamino- sulfonyl-2-indolinone 10727 D 73-[(1,4-benzopyranon-3-yl)- methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10727 D 8 3-(3-cyanobenzylidenyl)-5-methyl-aminosulfonyl-2-indolinone 10727 D 9 3-(4-cyanobenzylidenyl)-5-methyl-aminosulfonyl-2-indolinone 10727 D 10  3-(2,5-dihydroxybenzylodenyl)-5-methylaminosulfonyl-2-indolinone 10727 D 11 3-(2,3-dimethoxybenzylidenyl)-5- methylaminosulfonyl-2-indolinone 10727E 2 3-(4-diethylaminobenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl-2-indolinone 10727 E 3 3-[(2,4-diethylpyrrol-5-yl)methyl-idenyl]-5-[4-(trifluoromethyl)- phenylaminosulfonyl]-2-indolinone 10727E 4 3-(3-bromo-5-chloro-2-hydroxy- benzylidenyl)-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10727 E 53-[2-(4-chlorophenylmercapto)- benzylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10727 E 63-[(5-chlorobenzodioxolan-6-yl)- methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10727 E 73-[(1,4-benzopyranon-3-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonl]-2-indolinone 10727 E 8 3-(3-cyanobenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10727 E 93-(4-cyanobenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10727 E 10  3-(2,5-dihydroxybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl)-2-indolinone 10727 E 11 3-(2,3-dimethoxybenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10727 F 2 3-(4-diethylaminobenzylidenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10727 F 33-[(2,4-diethylpyrrol-5-yl)methyl- idenyl]-5-(morpholin-1-yl)sulfonyl-2-indolinone 10727 F 4 3-(3-bromo-5-chloro-2-hydroxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10727 F 53-[2-(4-chlorophenylmercapto)- benzylidenyl]-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10727 F 6 3-[(5-chlorobenzodioxolan-6-yl)-methylidenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10727 F 73-[(1,4-benzopyranon-3-yl)methyl- idenyl]-5-(morpholin-1-yl)sulfonyl-2-indolinone 10727 F 8 3-(3-cyanobenzylidenyl)-5-(morpholin-1-yl)sulfonyl-2-indolinone 10727 F 93-(4-cyanobenzylidenyl)-5-(morpholin- 1-yl)sulfonyl-2-indolinone 10727 F10  3-[2,5-dihydroxybenzylidenyl)-5- (morpholin-1-yl)sulfonyl-2-indolinone 10727 F 11  3-(2,3-dimethoxybenzylidenyl)-5-(morpholin-1-yl)sulfonyl-2- indolinone 10727 G 23-(4-diethylaminobenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10727 G 33-[(2,4-diethylpyrrol-5-yl)methyl- idenyl]-5-(2-chloroethyl)-2-indolinone 10727 G 4 3-(3-bromo-5-chloro-2-hydroxy-benzylidenyl)-5-(2-chloroethyl)- 2-indolinone 10727 G 53-[2-(4-chlorophenylmercapto)- benzylidenyl]-5-(2-chloroethyl)-2-indolinone 10727 G 6 3-[(5-chlorobenzodioxolan-6-yl)-methylidenyl]-5-(2-chloroethyl)- 2-indolinone 10727 G 73-[(1,4-benzopyranon-3-yl)methyl- idenyl]-5-(2-cloroethyl)-2- indolinone10727 G 8 3-(3-cyanobenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10727G 9 3-(4-cyanobenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10727 G 10 3-(2,5-dihydroxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10727 G11  3-(2,3-dimethoxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10728A 2 3-(2,5-dimethoxybenzylidenyl)- 5,7-dibromo-2-indolinone 10728 A 33-(2,6-dimethoxybenzylidenyl)- 5,7-dibromo-2-indolinone 10728 A 43-(3,5-dimethoxybenzylidenyl)- 5,7-dibromo-2-indolinone 10728 A 53-(4-dimethylamino-2-methoxy- benzylidenyl)-5,7-dibromo-2- indolinone10728 A 6 3-[(fluoren-2-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10728A 7 3-[2-fluoro-3-(trifluoromethyl)- benzylidenyl]-5,7-dibromo-2-indolinone 10728 A 8 3-[2-fluoro-5-(trifluoromethyl)-benzylidenyl-5,7-dibromo-2- indolinone 10728 A 93-[2-fluoro-6-(trifluoromethyl)- benzylidenyl]-5,7-dibromo-2- indolinone10728 A 10  3-(2-carboxymethoxybenzylidenyl)- 5,7-dibromo-2-indolinone10728 A 11  3-[(4-methoxybenzodioxolan-6-yl)-methylidenyl]-5,7-dibromo-2- indolinone 10728 B 23-(2,5-dimethoxybenzylidenyl)-5- iodo-2-indolinone 10728 B 33-(2,6-dimethoxybenzylidenyl)-5- iodo-2-indolinone 10728 B 43-(3,5-dimethoxybenzylidenyl)-5- iodo-2-indolinone 10728 B 53-(4-dimethylamino-2-methoxy- benzylidenyl)-5-iodo-2- indolinone 10728 B6 3-[(fluoren-2-yl)methylidenyl]- 5-iodo-2-indolinone 10728 B 73-[2-fluoro-3-(trifluoromethyl)- benzylidenyl]-5-iodo-2- indolinone10728 B 8 3-[2-fluoro-5-(trifluoromethyl)- benzylidenyl]-5-iodo-2-indolinone 10728 B 9 3-[2-fluoro-6-(trifluoromethyl)-benzylidenyl]-5-iodo-2- indolinone 10728 B 10 3-(2-carboxymethoxybenzylidenyl)-5- iodo-2-indolinone 10728 B 11 3-[(4-methoxybenzodioxolan-6-yl)- methyhdenyl]-5-iodo-2- indolinone10728 C 2 3-(2,5-dimethoxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone10728 C 3 3-(2,6-dimethoxybenzylidenyl)-5- bromo-4-methyl-2-indolinone10728 C 4 3-(3,5-dimethoxybenzylidenyl)-5- bromo-4-methyl-2-indolinone10728 C 5 3-(4-dimethylamino-2-methoxy- benzylidenyl)-5-bromo-4-methyl-2-indolinone 10728 C 6 3-[(fluoren-2-yl)methylidenyl]-5-bromo-4-methyl-2-indolinone 10728 C 7 3-[2-fluoro-3-(trifluoromethyl)-benzylidenyl]-5-bromo-4-methyl- 2-indolinone 10728 C 83-[2-fluoro-5-(trifluoromethyl)- benzylidenyl]-5-bromo-4-methyl-2-indolinone 10728 C 9 3-[2-fluoro-6-(trifluoromethyl)-benzylidenyl]-5-bromo-4-methyl- 2-indolinone 10728 C 10 3-(2-carboxymethoxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10728 C11  3-[(4-methoxybenzodioxolan-6-yl)- methylidenyl]-5-bromo-4-methyl-2-indolinone 10728 D 2 3-(2,5-dimethoxybenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10728 D 33-(2,6-dimethoxybenzylidenyl)-5- methylaminosulfonyl-2-indolinone 10728D 4 3-(3,5-dimethoxybenzylidenyl)-5- methylaminosulfonyl-2-indolinone10728 D 5 3-(4-dimethylamino-2-methoxy- benzylidenyl)-5-methylamino-sulfonyl-2-indolinone 10728 D 6 3-[(fluoren-2-yl)methyl-idenyl]-5-methylamino- sulfonyl-2-indolinone 10728 D 73-[2-fluoro-3-(trifluoro- methyl)benzylidenyl]-5-methyl-aminosulfonyl-2-indolinone 10728 D 8 3-[2-fluoro-5-(trifluoromethyl)-benzylidenyl]-5-methylamino- sulfonyl-2-indolinone 10728 D 93-[2-fluoro-6-(trifluoromethyl)- benzylidenyl]-5-methylamino-sulfonyl-2-indolinone 10728 D 10  3-(2-carboxymethoxybenzylidenyl)-5-methylaminosulfonyl-2- indolinone 10728 D 11 3-[(4-methoxybenzodioxolan-6-yl)- methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10728 E 2 3-(2,5-dimethoxybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10728 E 33-(2,6-dimethoxybenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10728 E 4 3-(3,5-dimethoxybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl)-2-indolinone 10728 E 53-(4-dimethylamino-2-methoxy- benzylidenyl)-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10728 E 63-[(fluoren-2-yl)methylidenyl]- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl-2-indolinone 10728 E 7 3-[2-fluoro-3-(trifluoromethyl)-benzylidenyl]-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10728 E 8 3-[2-fluoro-5-(trifluoromethyl)-benzylidenyl]-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10728 E 9 3-[2-fluoro-6-(trifluoromethyl)-benzylidenyl]-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10728 E 10  3-(2-carboxymethoxybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10728 E 11 3-[(4-methoxybenzodioxolan-6-yl)- methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10728 F 23-(2,5-dimethoxybenzylidenyl)-5- (morpholin-1-yl)aminosulfonyl-2-indolinone 10728 F 3 3-(2,6-dimethoxybenzylidenyl)-5-(morpholin-1-yl)aminosulfonyl- 2-indolinone 10728 F 43-(3,5-dimethoxybenzylidenyl)-5- (morpholin-1-yl)aminosulfonyl-2-indolinone 10728 F 5 3-(4-dimethylamino-2-methoxy-benzyudenyl)-5-(morpholin-1-yl)- aminosulfonyl-2-indolinone 10728 F 63-[(fluoren-2-yl)methylidenyl]- 5-(morpholin-1-yl)aminosulfonyl-2-indolinone 10728 F 7 3-[2-fluoro-3-(trifluoromethyl)-benzylidenyl]-5-(morpholin-1-yl)- aminosulfonyl-2-indolinone 10728 F 83-[2-fluoro-5-(trifluoromethyl)- benzylidenyl]-5-(morpholin-1-yl)-aminosulfonyl-2-indolinone 10728 F 9 3-[2-fluoro-6-(trifluoromethyl)-benzylidenyl]-5-(morpholin-1-yl)- aminosulfonyl-2-indolinone 10728 F 10 3-(2-carboxymethoxybenzylidenyl)- 5-(morpholin-1-yl)aminosulfonyl-2-indolinone 10728 F 11  3-[(4-methoxybenzodioxolan-6-yl)-methylidenyl]-5-(morpholin-1-yl)- aminosulfonyl-2-indolinone 10728 G 23-(2,5-dimethoxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10728 G 33-(2,6-dimethoxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10728 G 43-(3,5-dimethoxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10728 G 53-(4-dimethylamino-2-methoxybenzyl- idenyl)-5-(2-chloroethyl)-2-indolinone 10728 G 6 3-[(fluoren-2-yl)methylidenyl]-5-(2-chloroethyl)-2-indolinone 10728 G 73-[2-fluoro-3-(trifluoromethyl)- benzylidenyl]-5-(2-chloroethyl)-2-indolinone 10728 G 8 3-[2-fluoro-5-(trifluoromethyl)-benzylidenyl]-5-(2-chloroethyl)- 2-indolinone 10728 G 93-[2-fluoro-6-(trifluoromethyl)- benzylidenyl]-5-(2-chloroethyl)-2-indolinone 10728 G 10  3-(2-carboxymethoxybenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10728 G 11 3-[(4-methoxybenzodioxolan-6-yl)- methylidenyl]-5-(2-chloroethyl)-2-indolinone 10729 A 2 3-[(2-methoxynapth-1-yl)methyl-idenyl]-5,7-dibromo-2- indolinone 10729 A 33-[(1-methoxynapth-4-yl)methyl- idenyl]-5,7-dibromo-2- indolinone 10729A 4 3-(4-methylmercaptobenzylidenyl)- 5,7-dibromo-2-indolinone 10729 A 53-[(3-methylthien-2-yl)methyl- idenyl]-5,7-dibromo-2-indolinone 10729 A6 3-(3-phenoxybenzylidenyl)-5,7- dibromo-2-indolinone 10729 A 73-[(pyrid-2-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10729 A 83-[(pyrid-3-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10729 A 93-[(pyrid-4-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10729 A 10 3-[4-(pyrrolidin-1-yl)benzyl- idenyl]-5,7-dibromo-2- indolinone 10729 A11  3-[(cyctohexen-3-yl)methyl- idenyl]-5,7-dibromo-2- indolinone 10729B 2 3-[(2-methoxynapth-1-yl)methyl- idenyl]-5-iodo-2-indolinone 10729 B3 3-[(1-methoxynapth-4-yl)methyl- idenyl]-5-iodo-2-indolinone 10729 B 43-(4-methylmercaptobenzylidenyl)- 5-iodo-2-indolinone 10729 B 53-[(3-methylthien-2-yl)methyl- ideny]-5-iodo-2-indolinone 10729 B 63-(3-phenoxybenzylidenyl)-5- iodo-2-indolinone 10729 B 73-[(pyrid-2-yl)methylidenyl]- 5-iodo-2-indolinone 10729 B 83-[(pyrid-3-yl)methylidenyl]- 5-iodo-2-indolinone 10729 B 93-[(pyrid-4-yl)methylidenyl]- 5-iodo-2-indolinone 10729 B 10 3-[4-(pyrrolidin-1-yl)benzyl- idenyl]-5-iodo-2-indolinone 10729 B 11 3-[(cyclohexen-3-yl)methyl- idenyl]-5-iodo-2-indolinone 10729 C 23-[(2-methoxynapth-1-yl)methyl- idenyl)-5-bromo-4-methyl-2- indolinone10729 C 3 3-[(1-methoxynapth-4-yl)methyl- idenyl]-5-bromo-4-methyl-2-indolinone 10729 C 4 3-(4-methylmercaptobenzylidenyl)-5-bromo-4-methyl-2-indolinone 10729 C 5 3-[(3-methylthien-2-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10729 C 63-(3-phenoxybenzylidenyl)-5- bromo-4-methyl-2-indolinone 10729 C 73-[(pyrid-2-yl)methylidenyl]- 5-bromo-4-methyl-2-indolinone 10729 C 83-[(pyrid-3-yl)methylidenyl]-5- bromo-4-methyl-2-indolinone 10729 C 93-[(pyrid-4-yl)methylidenyl]-5- bromo-4-methyl-2-indolinone 10729 C 10 3-[4-(pyrrolidin-1-yl)benzyl- idenyl]-5-bromo-4-methyl-2- indolinone10729 C 11  3-[(cyclohexen-3-yl)methylidenyl]-5-bromo-4-methyl-2-indolinone 10729 D 2 3-[(2-methoxynapth-1-yl)methyl-idenyl)-5-methylaminosulfonyl- 2-indolinone 10729 D 33-[(1-metnoxynapth-4-yl)methyl- idenyl-5-methylaminosulfonyl-2-indolinone 10729 D 4 3-(4-methylmercaptobenzylidenyl)-5-methylaminosulfonyl-2- indolinone 10729 D 53-[(3-methylthien-2-yl)methyl- idenyl]-5-methylaminosulfonyl-2-indolinone 10729 D 6 3-(3-phenoxybenzylidenyl)-5-methyl-aminosulfonyl-2-indolinone 10729 D 7 3-[(pyrid-2-yl)methylidenyl]-5-methylaminosulfonyl-2-indolinone 10729 D 83-[(pyrid-3-yl)methylidenyl]-5- methylaminosulfonyl-2-indolinone 10729 A7 3-[(pyrid-2-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10729 A 83-[(pyrid-3-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10729 A 93-[(pyrid-4-yl)methylidenyl]- 5,7-dibromo-2-indolinone 10729 A 10 3-[4-(pyrrolidin-1-yl)benzyl- idenyl]-5,7-dibromo-2- indolinone 10729 A11  3-[(cyctohexen-3-yl)methyl- idenyl]-5,7-dibromo-2- indolinone 10729B 2 3-[(2-methoxynapth-1-yl)methyl- idenyl]-5-iodo-2-indolinone 10729 B3 3-[(1-methoxynapth-4-yl)methyl- idenyl]-5-iodo-2-indolinone 10729 B 43-(4-methylmercaptobenzylidenyl)- 5-iodo-2-indolinone 10729 B 53-[(3-methylthien-2-yl)methyl- ideny]-5-iodo-2-indolinone 10729 B 63-(3-phenoxybenzylidenyl)-5- iodo-2-indolinone 10729 B 73-[(pyrid-2-yl)methylidenyl]- 5-iodo-2-indolinone 10729 B 83-[(pyrid-3-yl)methylidenyl]- 5-iodo-2-indolinone 10729 B 93-[(pyrid-4-yl)methylidenyl]- 5-iodo-2-indolinone 10729 B 10 3-[4-(pyrrolidin-1-yl)benzyl- idenyl]-5-iodo-2-indolinone 10729 B 11 3-[(cyclohexen-3-yl)methyl- idenyl]-5-iodo-2-indolinone 10729 C 23-[(2-methoxynapth-1-yl)methyl- idenyl)-5-bromo-4-methyl-2- indolinone10729 C 3 3-[(1-methoxynapth-4-yl)methyl- idenyl]-5-bromo-4-methyl-2-indolinone 10729 C 4 3-(4-methylmercaptobenzylidenyl)-5-bromo-4-methyl-2-indolinone 10729 C 5 3-[(3-methylthien-2-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10729 C 63-(3-phenoxybenzylidenyl)-5- bromo-4-methyl-2-indolinone 10729 C 73-[(pyrid-2-yl)methylidenyl]- 5-bromo-4-methyl-2-indolinone 10729 C 83-[(pyrid-3-yl)methylidenyl]-5- bromo-4-methyl-2-indolinone 10729 C 93-[(pyrid-4-yl)methylidenyl]-5- bromo-4-methyl-2-indolinone 10729 C 10 3-[4-(pyrrolidin-1-yl)benzyl- idenyl]-5-bromo-4-methyl-2- indolinone10729 C 11  3-[(cyclohexen-3-yl)methylidenyl]-5-bromo-4-methyl-2-indolinone 10729 D 2 3-[(2-methoxynapth-1-yl)methyl-idenyl)-5-methylaminosulfonyl- 2-indolinone 10729 D 33-[(1-metnoxynapth-4-yl)methyl- idenyl-5-methylaminosulfonyl-2-indolinone 10729 D 4 3-(4-methylmercaptobenzylidenyl)-5-methylaminosulfonyl-2- indolinone 10729 D 53-[(3-methylthien-2-yl)methyl- idenyl]-5-methylaminosulfonyl-2-indolinone 10729 D 6 3-(3-phenoxybenzylidenyl)-5-methyl-aminosulfonyl-2-indolinone 10729 D 7 3-[(pyrid-2-yl)methylidenyl]-5-methylaminosulfonyl-2-indolinone 10729 D 83-[(pyrid-3-yl)methylidenyl]-5- methylaminosulfonyl-2-indolinone 10729 D9 3-[(pyrid-4-yl)methylidenyl]-5- methylaminosulfonyl-2-indolinone 10729D 10  3-[4-(pyrrolidin-1-yl)benzyl- idenyl]-5-methylaminosulfonyl-2-indolinone 10729 D 11  3-[(cyclohexen-3-yl)methyl-idenyl]-5-methylaminosulfonyl- 2-indolinone 10729 E 23-[(2-methoxynath-1-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2- indolinone 10729 E 33-[(1-methoxynapth-4-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10729 E 43-(4-methylmercaptobenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10729 E 5 3-[(3-methylthien-2-yl)methyl-idenyl]-5-[4-(trifluoromethyl)- phenylaminosulfonyl-2-indolinone 10729 E6 3-(3-phenoxybenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl)-2-indolinone 10729 E 7 3-[(pyrid-2-yl)meyhylidenyl]-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10729 E 83-[(pyrid-3-yl)meyhylidenyl]-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10729 E 9 3-[(pyrid-4-yl)meyhylidenyl]-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10729 E 10 3-[4-(pyrrolidin-1-yl)benzyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl)-2-indolinone 10729 E 11 3-[(cyclohexen-3-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10729 F 23-[(2-methoxynapth-1-yl)methyl- idenyl]-5-(morpholin-1-yl)amino-sulfonyl-2-indolinone 10729 F 3 3-[(1-methoxynapth-4-yl)methyl-idenyl]-5-(morpholin-1-yl)amino- sulfonyl-2-indolinone 10729 F 43-(4-methylmercaptobenzylidenyl)-5- (morpholin-1-yl)aminosulfonyl-2-indolinone 10729 F 5 3-[(3-methylthien-2-yl)methyl-idenyl]-5-(morpholin-1-yl)- aminosulfonyl-2-indolinone 10729 F 63-(3-phenoxybenzylidenyl)-5- (morpholin-1-yl)aminosulfonyl- 2-indolinone10729 F 7 3-[(pyrid-2-yl)methylidenyl]-5- (morpholin-1-yl)aminosulfonyl-2-indoiinone 10729 F 8 3-[(pyrid-3-yl)methylidenyl]-5-(morpholin-1-yl)aminosulfonyl- 2-indoiinone 10729 F 93-[(pyrid-4-yl)methylidenyl]-5- (morpholin-1-yl)aminosulfonyl-2-indoiinone 10729 F 10  3-[4-(pyrrolidin-1-yl)benzyl-idenyl]-5-(morpholin-1-yl)- aminosulfonyl-2-indolinone 10729 F 11 3-[(cyclohexen-3-l)methyl- idenyl]-5-(morpholin-1-yl)-aminosulfonyl-2-indolinone 10729 G 2 3-[(2-methoxynapth-1-yl)methyl-idenyl]-5-(2-chloroethyl)- 2-indolinone 10729 G 33-[(1-methoxynapth-4-yl)methyl- idenyl]-5-(2-chloroethyl)- 2-indolinone10729 G 4 3-(4-methylmercaptobenzyl- idenyl)-3-(2-chloroethyl)-2-indolinone 10729 G 5 3-[(3-methylthien-2-yl)methyl-idenyl]-5-(2-chloroethyl)- 2-indolinone 10729 G 63-(3-phenoxybenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10729 G 73-[(pyrid-2-yl)methylidenyl]-5-(2- chloroethyl)-2-indolinone 10729 G 83-[(pyrid-3-yl)methylidenyl]-5-(2- chloroethyl)-2-indolinone 10729 G 93-[(pyrid-4-yl)methylidenyl]-5-(2- chloroethyl)-2-indolinone 10729 G 10 3-[4-(pyrrolidin-1-yl)benzyl- idenyl]-5-(2-chloroethyl)-2- indolinone10729 G 11  3-((cyclohexen-3-yl)methylidenyl]-5-(2-chloroethyl)-2-indolinone 10730 A 2 3-(2,3,4-trimethoxybenzylidenyl)-5,7-dibromo-2-indolinone 10730 A 3 3-(2,4,5-trimethoxybenzylidenyl)-5,7-dibromo-2-indolinone 10730 A 4 3-(3,4,5-trimethoxybenzylidenyl)-5,7-dibromo-2-indolinone 10730 A 5 3-[(1-acetylindol-3-yl)methyl-idenyl]-5,7-dibromo-2-indolinone 10730 A 63-[(6-chloro-1,4-benzofuranon-3-yl)- methylidenyl]-5,7-dibromo-2-indolinone 10730 A 7 3-[2-[(2-chlorophenyl)furan-5-yl)-methylidenyl]-5,7-dibromo-2- indolinone 10730 A 83-[(2-chloroquinolin-3-yl)methyl- idenyl]-5,7-dibromo-2-indolinone 10730A 9 3-[(6,8-dibromo-1,4-benzofuranon-3- yl)methylidenyl]-5,7-dibromo-2-indolinone 10730 A 10  3-[(2,5-dimethoxytetrahydrofuran-3-yl)methylidenyl]-5,7-dibromo-2- indolinone 10730 A 11 3-[(2,3-dimethylfuran-5-yl)methyl- idenyl]-5,7-dibromo-2- indolinone10730 B 2 3-(2,3,4-trimethoxybenzylidenyl)- 5-iodo-2-indolinone 10730 B3 3-(2,4,5-trimethoxybenzylidenyl)-5- iodo-2-indolinone 10730 B 43-(3,4,5-trimethoxybenzylidenyl)-5- iodo-2-indolinone 10730 B 53-[(1-acetylindol-3-yl)methyl- idenyl]-5-iodo-2-indolinone 10730 B 63-[(6-chloro-1,4-benzofuranon- 3-yl)methylidenyl]-5-iodo-2- indolinone10730 B 7 3-[2-[(2-chlorophenyl)furan-5- yl]methylidenyl]-5-iodo-2-indolinone 10730 B 8 3-[(2-chloroquinolin-3-yl)methyl-idenyi]-5-iodo-2-indolinone 10730 B 9 3-[(6,8-dibromo-1 ,4-benzo-furanon-3-yl)methylidenyl]-5- iodo-2-indolinone 10730 B 10 3-[(2,5-dimethoxytetrahydrafuran- 3-yl)methylidenyl]-5-iodo-2-indolinone 10730 B 11  3-[(2,3-dimethylfuran-5-yl)-methylidenyl]-5-iodo-2- indolinone 10730 C 23-(2,3,4-trimethoxybenzylidenyl)-5- bromo-4-methyl-2-indolinone 10730 C3 3-(2,4,5-trimethoxybenzylidenyl)-5- bromo-4-methyl-2-indolinone 10730C 4 3-(3,4,5-trimethoxybenzylidenyl)-5- bromo-4-methyl-2-indolinone10730 C 5 3-[(1-acetylindol-3-yl)methyl- idenyl]-5-bromo-4-methyl-2-indolinone 10730 C 6 3-[(6-chloro-1,4-benzofuranon-3-yl)-methylidenyl]-5-bromo-4-methyl- 2-indolinone 10730 C 73-[2-[(2-chlorophenyl)furan-5-yl)- methylidenyl]-5-bromo-4-methyl-2-indolinone 10730 C 8 3-[(2-chloroquinolin-3-yl)methyl-idenyl]-5-bromo-4-methyl-2- indolinone 10730 C 9 3-[(6,8-dibromo-1,4-benzo- furanon-3-yl)methylidenyl]-5- iodo-2-indolinone 10730 C 10 3-[(2,5-dimethoxytetrahydrafuran- 3-yl)methylidenyl]-5-iodo-2-indolinone 10730 C 11  3-[(2,3-dimethylfuran-5-yl)-methylidenyl]-5-iodo-2- indolinone 10730 D 23-(2,3,4-trimethoxybenzylidenyl)- 5-methylaminosulfonyl-2- indolinone10730 D 3 3-(2,4,5-trimethoxybenzylidenyl)- 5-methylaminosulfonyl-2-indolinone 10730 D 4 3-(3,4,5-trimethoxybenzylidenyl)-5-methylaminosulfonyl-2- indolinone 10730 D 53-[(1-acetylindol-3-yl)methyl- idenyl]-5-methylaminosulfonyl-2-indolinone 10730 D 6 3-[(6-chloro-1,4-benzofuranon-3-yl)methylidenyl)-5-methylamino- sulfonyl-2-indolinone 10730 D 73-[2-[(2-chlorophenyl)furan-5- yl]methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10730 D 8 3-[(2-chloroquinolin-3-yl)methyl-idenyl]-5-methylaminosulfonyl- 2-indolinone 10730 D 93-[(6,8-dibromo-1,4-benzofuranon- 3-yl)methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10730 D 10  3-[(2,5-dimethoxytetrahydrofuran-3-yl)methylidenyl]-5-methylamino- sulfonyl-2-indolinone 10730 D 11 3-[(2,3-dimethylfuran-5-yl)methyl- idenyl]-5-methylaminosulfonyl-2-indolinone 10730 E 2 3-(2,3,4-trimethoxybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10730 E 33-(2,4,5-trimethoxybenzylidenyl)-5- [4-(trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10730 E 4 3-(3,4,5-trimethoxybenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10730 E 53-[(1-acetylindol-3-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10730 E 63-[(6-chloro-1,4-benzofuranon-3-yl)- methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]-2- indolinone 10730 E 73-[2-[(2-chlorophenyl)furan-5-yl]- methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]-2- indolinone 10730 E 83-[(2-chloroquinolin-3-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10730 E 93-[(6,8-dibromo-1,4-benzofuranon-3- yl)methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10730 E 10 3-[(2,5-dimethoxytetrahydrofuran-3- yl)methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10730 E 11 3-[(2,3-dimethylfuran-5-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10730 F 23-(2,3,4-trimethoxybenzylidenyl)-5- (morpholin-1-yl)sulfonyl-2-indolinone 10730 F 3 3-(2,4,5-trimethoxybenzylidenyl)-5-(morpholin-1-yl)sulfonyl-2- indolinone 10730 F 43-(3,4,5-trimethoxybenzylidenyl)-5- (morpholin-1-yl)sulfonyl-2-indolinone 10730 F 5 3-[(1-acetylindol-3-yl)methyl-idenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10730 F 63-[(6-chloro-1,4-benzafuranon-3- yl)methylidenyl]-5-(morpholin-1-yl)sulfonyl-2-indolinone 10730 F 7 3-[2-[(2-chlorophenyl)furan-5-yl]methylidenyl]-5-(morpholin-1- yl)sulfonyl-2-indolinone 10730 F 83-[(2-chloroquinolin-3-yl)methyl- idenyl]-5-(morpholin-1-yl)sulfonyl-2-indolinone 10730 F 9 3-[(6,8-dibromo-1,4-benzofuranon-3-yl)methylidenyl]-5-(morpholin-1- yl)sulfonyl-2-indolinone 10730 F 10 3-[(2,5-dimethoxytetrahydrofuran-3- yl)methylidenyl]-5-(morpholin-1-yl)sulfonyl-2-indolinone 10730 F 11  3-[(2,3-dimethylfuran-5-yl)methyl-idenyl]-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10730 G 23-(2,3,4-trimethoxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10730 G3 3-(2,4,5-trimethoxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone 10730G 4 3-(3,4,5-trimethoxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone10730 G 5 3-[(1-acetylindol-3-yl)methyl- idenyl]-5-(2-chloroethyl)-2-indolinone 10730 G 6 3-[(6-chloro-1,4-benzofuranon-3-yl)methylidenyl]-5-(2-chloroethyl)- 2-indolinone 10730 G 73-[2-[(2-chlorophenyl)furan-5- yl]methylidienyl]-5-(2-chloroethyl)-2-indolinone 10730 G 8 3-[(2-chloroquinolin-3-yl)methyl-idenyl]-5-(2-chloroethyl)-2- indolinone 10730 G 93-[(6,8-dibromo-1,4-benzofuranon- 3-yl)methylidenyl]-5-(2-chloroethyl)-2-indolinone 10730 G 10 3-[(2,5-dimethoxytetrahydrofuran-3- yl)methylidenyl]-5-(2-chloiroethyl)-2-indolinone 10730 G 11  3-[(2,3-dimethylfuran-5-yl)methyl-idenyl]-5-(2-chloroethyl)-2- indolinone 10731 A 23-[(9-ethylcarbazol-3-yl)methyl- idenyl]-5,7-dibromo-2-indolinone 10731A 3 3-[(6,7-dimethyl-1,4-benzopyron-3- yl)methylidenyl]-5,7-dibromo-2-indolinone 10731 A 4 3-[[4-(Propen-2-yl)cyclohexen-1-yl]methylidenyl]-5,7-dibromo-2- indolinone 10731 A 53-[(6-isopropyl-1,4-benzopyron-3-yl)- methylidenyl]-5,7-dibromo-2-indolinone 10731 A 6 3-[(6-methyl-1,4-benzopyron-3-yl)-methylidenyl]-5,7-dibromo-2- indolinone 10731 A 73-[(6-nitro-1,4-benzopyron-3-yl)- methylidenyl]-5,7-dibromo-2-indolinone 10731 A 8 3-[(pyrimid-2,4-dion-5-yl)methyl-idenyl]-5,7-dibromo-2-indolinone 10731 A 93-[(5-methoxyindol-3-yl)methyl- idenyl]-5,7-dibromo-2-indolinone 10731 A10  3-(1-methyl-2-oxindol-3-idenyl)-5,7- dibromo-2-indolinone 10731 A11  3-[2-[2-(nitrophenyl)furan-5-yl]- methylidenyl]-5,7-dibromo-indolinone 10731 B 2 3-[(9-ethylcarbazol-3-yl)methyl-idenyl]-5-iodo-2-indolinone 10731 B 33-[(6,7-dimethyl-1,4-benzopyron-3-yl)- methylidenyl]-5-iodo-2-indolinone10731 B 4 3-[[4-(propen-2-yl)cyclohexen-l-yl]- methylidenyI]-5-iodo-2-indolinone 10731 B 5 3-[(6-isopropyl-1,4-benzopyron-3-yl)-methylidenyl]-5-iodo-2-indolinone 10731 B 63-[(6-methyl-1,4-benzopyron-3-yl)- methylidenyl]-5-iodo-2-indolinone10731 B 7 3-[(6-nitro-1,4-benzopyron-3-yl)-methylidenyl]-5-iodo-2-indolinone 10731 B 83-[(pyrimid-2,4-dion-5-yl)methyl- idenyl]-5-iodo-2-indolinone 10731 B 93-[(5-methoxyindol-3-yl)methyl- idenyl]-5-iodo-2-indolinone 10731 B 10 3-(1-methyl-2-oxindol-3-idenyl)-5- iodo-2-indolinone 10731 B 11 3-[2-[2-(nitrophenyl)furan-5- yl]methylidenyl]-5-iodo-2- indolinone10731 C 2 3-[(9-ethylcarbazol-3-yl)methyl- idenyl]-5-bromo-4-methyl-2-indolinone 10731 C 3 3-[(6,7-dimethyl-1,4-benzopyron-3-yl)-methylidenyl]-5-bromo-4-methyl- 2-indolinone 10731 C 43-[[4-(propen-2-yl)cyclohexen-1- yl)methylidenyl]-5-bromo-4-methyl-2-indolinone 10731 C 5 3-[(6-isopropyl-1,4-benzopyron-3-yl)methylidenyl]-5-bromo-4-methyl- 2-indolinone 10731 C 63-[(6-methyl-1,4-benzopyron-3-yl)- methylidenyl]-5-bromo-4-methyl-2-indolinone 10731 C 7 3-[(6-nitro-1,4-benzopyran-3-yl)-methylidenyl]-5-bromo-4-methyl- 2-indolinone 10731 C 83-[(pyrimid-2,4-dion-5-yl)methyl- idenyl]-5-bromo-4-methyl- 2-indolinone10731 C 9 3-[(5-methoxyindol-3-yl)methyl- idenyl]-5-bromo-4-methyl-2-indolinone 10731 C 10  3-(1-methyl-2-oxindol-3-idenyl)-5-bromo-4-methyl-2-indolinone 10731 C 11 3-[2-[2-(nitrophenyl)furan-5-yl)- methylidenyl]-5-bromo-4-methyl-2-indolinone 10731 D 2 3-[(9-ethylcarbazol-3-yl)methyl-idenyl]-5-methylaminosulfonyl- 2-indolinone 10731 D 33-[(6,7-dimethyl-1,4-benzopyron-3- yl)methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10731 D 4 3-[[4-(propen-2-yl)cyclohexen-1-yl]methylidenyl]-5-methylamino- sulfonyl-2-indolinone 10731 D 53-[(6-isopropyl-1,4-benzopyron-3- yl)methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10731 D 6 3-[(6-methyl-1,4-benzopyron-3-yl)-methyldenyl]-5-methylamino- sulfonyl-2-indolinone 10731 D 73-[(6-nitro-1,4-benzopyrorl-3-yl)- methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10731 D 8 3-[(pyrimid-2,4-dion-5-yl)methyl-idenyl]-5-methylaminosulfonyl- 2-indolinone 10731 D 93-[(5-methoxyindol-3-yl)methyl- idenyl]-5-methylaminosulfonyl-2-indolinone 10731 D 10  3-(1-methyl-2-oxindol-3-idenyl)-5-methylaminosulfonyl-2-indolinone 10731 D 11 3-[2-[2-(nitrophenyl)furan-5-yl)- methylidenyl]-5-methylamino-sulfonyl-2-indolinone 10731 E 2 3-[(9-ethylcarbazol-3-yl)methyl-idenyl]-5-[4-(trifluoromethyl)- phenylaminosulfonyl]-2- indolinone 10731E 3 3-[(6,7-dimethyl-1,4-benzopyron-3- yl)methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]-2- indolinone 10731 E 43-[[4-(propen-2-yl)cyclohexen-1- yl]methylidenyl]-5-[4-(tri-fluoromethyl)phenylaminosulfonyl]- 2-indolinone 10731 E 53-[(6-isopropyl-1,4-benzopyron-3- yl)methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl]-2- indolinone 10731 E 63-[(6-methyl-1,4-benzopyron-3-yl)- methylidenyl]-5-[4-(trifluoro-methyl)phenylaminosulfonyl)-2- indolinone 10731 E 73-[6-nitro-1,4-benzopyron-3-yl)- methylidenyfl-5-[4-(tifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10731 E 83[(pyrimid-2,4-dion-5-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10731 E 93-[(5-methoxyindol-3-yl)methyl- idenyl]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2- indolinone 10731 E 10 3-(1-methyl-2-oxindol-3-idenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10731 E 11  3-[2-[2-(nitrophenyl)furan-5-yl]methylidenyl]-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10731 F 2 3[(9-ethylcarbazol-3-yl)methyl-idenyl]-5-(morpholin-1-yl) sulfonyl-2-indolinone 10731 F 33-[(6,7-dimethyl-1,4-benzopyron- 3-yl)methylidenyl]-5-(morpholin-1-yl)sulfonyl-2-indolinone 10731 F 4 3-[[4-(propen-2-yl)cyclohexen-1-yl]methylidenyl]-5-(morpholin- 1-yl)sulfonyl-2-indolinone 10731 F 53-[(6-isopropyl-1,4-benzopyron-3- yl)methylidenyl]-5-(morpholin-1-yl)sulfonyl-2-indolinone 10731 F 6 3-[(6-methyl-1,4-benzopyron-3-yl)-methylidenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10731 F 73-[(6-nitro-1,4-benzopyron-3-yl)- methylidenyl]-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10731 F 8 3-[(pyrimid-2,4-dion-5-yl)methyl-idenyl]-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10731 F 93-[(5-methoxyindol-3-yl)methyl- idenyl]-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10731 F 10  3-(1-methyl-2-oxindol-3-idenyl]-5-(morpholin-1-yl)sulfonyl-2- indolinone 10731 F 11 3-[2-[2-(nitrophenyl)furan-5-yl]- methylidenyl]-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10731 G 2 3-[(9-ethylcarbazol-3-yl)methyl-idenyl]-5-(2-chloroethyl)-2- indolinone 10731 G 33-[(6,7-dimethyl-1,4-benzopyron-3- yl)methylidenyl]-5-(2-chloroethyl)-2-indolinone 10731 G 4 3-[[4-(propen-2-yl)cyclohexen-1-yl]methylidenyl]-5-(2-chloroethyl)- 2-indolinone 10731 G 53-[(6-isopropyl-1,4-benzopyron-3-yl)- methylidenyl]-5-(2-chloroethyl)-2-indolinone 10731 G 6 3-[(6-methyl-1,4-benzopyron-3-yl)-methylidenyl]-5-(2-chloroethyl)- 2-indolinone 10731 G 73-[(6-nitro-1,4-benzopyron-3-yl)- methylidenyl]-5-(2-chloroethyl)-2-indolinone 10731 G 8 3-[(pyrimid-2,4-dion-5-yl)methyl-idenyl]-5-(2-chloroethyl)-2- indolinone 10731 G 93-[(5-methoxyindol-3-yl)methyl- idenyl]-5-(2-chloroethyl)- 2-indolinone10731 G 10  3-(1-methyl-2-oxindol-3-idenyl)-5-(2-chloroethyl)-2-indolinone 10731 G 11  3-[2-[2-(nitrophenyl)furan-5-yl]-methylidenyl]-5-(2- chloroethyl)-2-indolinone 10732 A 23-[2-(thien-2-yl)-2-(trifluoro- methyl]ethylidenyl]-5,7-dibromo-2-indolinone 10732 A 3 3-(3,5-diisopropyl-4-methoxybenzyl-idenyl)-5,7-dibromo-2-indolinone 10732 A 4 3-(3,5-diisopropyl-4-phenoxy-benzylidenyl)-5,7-dibromo-2- indolinone 10732 A 5(3-[-butyl-4-methoxybenzyl- idenyl)-5,7-dibromo-2-indolinone 10732 A 63-(4-benzyloxy-3-t-butylbenzyl- idenyl)-5,7-dibromo-2-indolinone 10732 A7 3-(3-bromo-5-t-butyl-4-methoxy- benzylidenyl)-5,7-dibromo-2-indolinone 10732 A 8 3-(4-benzyloxy-3-bromo-5-t-butyl-benzylidenyl)-5,7-dibromo-2- indolinone 10732 A 93-(3-t-butyl-5-chloro-4-methoxy- benzylidenyl)-5,7-dibromo-2- indolinone10732 A 10  3-(4-benzyloxy-5-t-butyl-3- chlorobenzylidenyl)-5,7-dibromo-2-indolinone 10732 A 11  3-(3-t-butyl-5-iodo-4-methoxy-benzylidenyl)-5,7-dibromo-2- indolinone 10732 B 23-[2-(thien-2-yl)-2-(trifluoro- methyl)ethylidenyl]-5-iodo- 2-indolinone10732 B 3 3-(3,5-diisopropyl-4-methoxybenzyl-idenyl)-5-iodo-2-indolinone 10732 B 43-(3,5-diisopropyl-4-phenoxybenzyl- idenyl)-5-iodo-2-indolinone 10732 B5 3-(3-t-butyl-4-methoxybenzylidenyl)- 5-iodo-2-indolinone 10732 B 63-(4-benzyloxy-3-t-butylbenzyl- idenyl)-5-iodo-2-indolinone 10732 B 73-(3-bromo-5-t-butyl-4-methoxy- benzylidenyl)-5-iodo-2-indolinone 10732B 8 3-(4-benzyloxy-3-bromo-5-t-butyl- benzylidenyl)-5-iodo-2-indolinone10732 B 9 3-(3-t-butyl-5-cloro-4-methoxy-benzylidenyl)-5-iodo-2-indolinone 10732 B 10 3-(4-benzyloxy-5-t-butyl-3-chloro- benzylidenyl)-5-iodo-2-indolinone10732 B 11  3-(3-t-butyl-5-iodo-4-methoxy-benzylidenyl)-5-iodo-2-indolinone 10732 C 23-(2-(thien-2-yl)-2-(trifluoro- methyl)ethylidenyl]-5-bromo-4-methyl-2-indolinone 10732 C 3 3-(3,5-diisopropyl-4-methoxybenzyl-idenyl)-5-bromo-4-methyl-2- indolinone 10732 C 43-(3,5-diisopropyl-4-phenoxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10732 C 5 3-(3-t-butyl-4-methoxybenzylidenyl)-5-bromo-4-methyl-2-indolinone 10732 C 6 3-(4-benzyloxy-3-t-butylbenzyl-idenyl)-5-bromo-4-methyl-2- indolinone 10732 C 73-(3-bromo-5-t-butyl-4-methoxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10732 C 8 3-(4-benzyloxy-3-bromo-5-t-butyl-benzylidenyl)-5-bromo-4-methyl- 2-indolinone 10732 C 93-(3-t-butyl-5-chloro-4-methoxy- benzylidenyl)-5-bromo-4-methyl-2-indolinone 10732 C 10  3-(4-benzyloxy-5-t-butyl-3-chloro-benzylidenyl)-5-bromo-4-methyl- 2-indolinone 10732 C 11 3-(3-t-butyl-5-iodo-4-methoxy- benzylidenyl)-5-bromo-4-methyl-2-indolinone 10732 D 2 3-[2-(thien-2-yl)-2-(trifluoro-methyl)ethylidenyl]-5-methyl- aminosulfonyl-2-indolinone 10732 D 33-(3,5-diisopropyl-4-methoxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10732 D 4 3-(3,5-diisopropyl-4-phenoxy-benzylidenyl)-5-methylamino- sulfonyl-2-indolinone 10732 D 53-(3-t-butyl-4-methoxybenzylidenyl)- 5-methylaminosulfonyl-2-indolinone10732 D 6 3-(4-benzyloxy-3-t-butylbenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10732 D 7 3-(3-bromo-5-t-butyl-4-methoxybenzyl-idenyl)-5-methylaminosulfonyl- 2-indolinone 10732 D 83-(4-benzyloxy-3-bromo-5-t-butyl- benzylidenyl)-5-methylamino-sulfonyl-2-indolinone 10732 D 9 3-(3-t-butyl-5-chloro-4-methoxy-benzylidenyl)-5-methylamino- sulfonyl-2-indolinone 10732 D 10 3-(4-benzyloxy-5-t-butyl-3-chloro- benzylidenyl)-5-methylamino-sulfonyl-2-indolinone 10732 D 11  3-(3-t-butyl-5-iodo-4-methoxybenzyl-idenyl)-5-methylaminosulfonyl- 2-indolinone 10732 E 23-[2-(thien-2-yl)-2-(trifluoro- methyl)ethylidenyl)-5-[4-(tri-fluoromethyl)phenylaminosulfonyl)- 2-indolinone 10732 E 33-(3,5-diisopropyl-4-methoxybenzyl-idenyl)-5-[4-(trifluoromethyl)phenyl- aminosulfonyl]-2-indolinone 10732E 4 3-(3,5-diisopropyl-4-phenoxybenzyl- ideny)]-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10732 E 53-(3-t-butyl-4-methoxybenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10732 E 63-(4-benzyloxy-3-t-butylbenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosuIlfonyl)-2-indolinone 10732 E 73-(3-bromo-5-t-butyl-4-methoxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10732 E 83-(4-benzyloxy-3-bromo-5-t-butyl- benzylidenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10732 E 93-(3-t-butyl-5-chloro-4-methoxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10732 E 10 3-(4-benzyloxy-5-t-butyl-3-chlorobenzyl- idenyl)-6-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10732 E 11 3-(3-t-butyl-5-iodo-4-methoxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10732 F 23-[2-(thien-2-yl)-2-(trifluoro- methyl)ethylidenyl]-5-2-(morpholin-1-yl)sulfonyl-2-indolinone 10732 F 3 3-(3,5-diisopropyl-4-methoxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10732 F 43-(3,5-diisopropyl-4-phenoxybenzyl- idenyl)-5-(morpholin-1-yl)sulfonyl-2-indolinone 10732 F 5 3-(3-t-butyl-4-methoxybenzylidenyl)-5-(morpholin-1-yl)sulfonyl-2- indolinone 10732 F 63-(4-benzyloxy-3-t-butylbenzylidenyl)- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10732 F 7 3-(3-bromo-5-t-butyl-4-methoxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10732 F 83-(4-benzyloxy-3-bromo-5-t-butylbenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10732 F 93-(3-t-butyl-5-chloro-4-methoxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10732 F 10 3-(4-benzyloxy-5-t-butyl-3-chloro- benzylidenyl)-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10732 F 11  3-(3-t-butyl-5-iodo-4-methoxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10732 G 23-[2-(thien-2-yl)-2-(trifluoromethyl)- ethylidenyl]-5-(2-chloroethyl)-2-indolinone 10732 G 3 3-(3,5-diisopropyl-4-methoxybenzyl-idenyl]-5-(2-chloroethyl)-2- indolinone 10732 G 43-(3,5-diisopropyl-4-phenoxybenzyl-idenyl)-5-(2-chloroethyl)-2-indolinone 10732 G 53-(3-t-butyl-4-methoxybenzylidenyl)-5- (2-chloroethyl)-2-indolinone10732 G 6 3-(4-benzyloxy-3-t-butylbenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10732 G 73-(3-bromo-5-t-butyl-4-methoxybenzyl-idenyl)-5-(2-chloroethyl-2-indolinone 10732 G 83-(4-benzyloxy-3-bromo-5-t-butylbenzyl- idenyl)-5-(2-chloroethyl)-2-indolinone 10732 G 9 3-(3-t-butyl-5-chloro-4-methoxybenzyl-idenyl)-5-(2-chloroethyl)-2-indolinone 10732 G 10 3-(4-benzyloxy-5-t-butyl-3-chlorobenzyl- idenyl)-5-(2-chloroethyl)-2-indolinone 10732 G 11  3-(3-t-butyl-5-iodo-4-methoxybenzyl-idenyl)-5-(2-chloroethyl)-2-indolinone 10733 A 23-(4-benzyloxy-3-t-butyl-5-iodobenzyl- idenyl)-5,7-dibromo-2-indolinone10733 A 3 3-(3-t-butyl-methoxy-5-nitrobenzyl-idenyl)-5,7-dibromo-2-indolinone 10733 A 43-(3,5-di-t-butyl-4-methoxybenzyl- idenyl)-5,7-dibromo-2-indolinone10733 A 5 3-(4-benzyloxy-3,5-di-t-butylbenzyl-idenyl)-5,7-dibromo-2-indolinone 10733 A 63-(3,5-dimethyl-4-methoxybenzyl- idenyl)-5,7-dibromo-2-indolinone 10733A 7 3-(4-benzyloxy-3,5-dimethylbenzyl- idenyl)-5,7-dibromo-2-indolinone10733 A 8 3-(5-bromo-2-hydroxy-3-methoxybenzyl-idenyl)-5,7-dibromo-2-indolinone 10733 A 93-(5-bromo-2-hydroxybenzylidenyl)- 5,7-dibromo-2-indolinone 10733 A 10 3-(2-hydroxy-5-nitrobenzylidenyl)- 5,7-dibromo-2-indolinone 10733 A 11 3-(4-hydroxy-3-methoxy-2-nitro- benzylidenyl)-5,7-dibromo-2- indolinone10733 B 2 3-(4-benzyloxy-3-t-butyl-5-iodo-benzylidenyl)-5-iodo-2-indolinone 10733 B 33-(3-t-butyl-4-methoxy-5-nitrobenzyl- idenyl)-5-iodo-2-indolinone 10733B 4 3-(3,5-di-t-butyl-4-methoxybenzyl- idenyl)-5-iodo-2-indolinone 10733B 5 3-(4-benzyloxy-3,5-di-t-butylbenzyl- idenyl)-5-iodo-2-indolinone10733 B 6 3-(3,5-dimethyl-4-methoxybenzyl- idenyl)-5-iodo-2-indolinone10733 B 7 3-(4-benzyloxy-3,5-dimethylbenzyl- idenyl)-5-iodo-2-indolinone10733 B 8 3-(5-bromo-2-hydroxy-3-methoxy-benzylidenyl)-5-iodo-2-indolinone 10733 B 93-(5-bromo-2-hydroxybenzylidenyl)- 5-iodo-2-indolinone 10733 B 10 3-(2-hydroxy-5-nitrobenzylidenyl)- 5-iodo-2-indolinone 10733 B 11 3-(4-hydroxy-3-methoxy-2-nitro- benzylidenyl)-5-iodo-2-indolinone 10733C 2 3-(4-benzyloxy-3-t-butyl-5-iodo- benzylidenyl)-5-bromo-4-methyl-2-indolinone 10733 C 3 3-(3-t-butyl-4-methoxy-5-nitro-benzylidenyl)-5-bromo-4-methyl- 2-indolinone 10733 C 43-(3,5-di-t-butyl-4-methoxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10733 C 5 3-(4-benzyloxy-3,5-di-t-butylbenzyl-idenyl)-5-bromo-4-methyl-2- indolinone 10733 C 63-(3,5-dimethyl-4-methoxybenzyl- idenyl)-5-bromo-4-methyl-2- indolinone10733 C 7 3-(4-benzyloxy-3,5-dimethylbenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10733 C 8 3-(5-bromo-2-hydroxy-3-methoxy-benzylidenyl)-5-bromo-4-methyl- 2-indolinone 10733 C 93-(5-bromo-2-hydroxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10733 C10  3-(2-hydroxy-5-nitrobenzylidenyl)- 5-bromo-4-methyl-2-indolinone10733 C 11  3-(4-hydroxy-3-methoxy-2-nitro-benzylidenyl)-5-bromo-4-methyl- 2-indolinone 10733 D 23-(4-benzyloxy-3-t-butyl-5-iodo- benzylidenyl)-5-methylamino-sulfonyl-2-indolinone 10733 D 3 3-(3-t-butyl-4-methoxy-5-nitro-benzylidenyl)-5-methylamino- sulfonyl-2-indolinone 10733 D 43-(3,5-di-t-butyl-4-methoxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10733 D 5 3-(4-benzyloxy-3,5-di-t-butyl-benzylidenyl)-5-methylamino- sulfonyl-2-indolinone 10733 D 63-(3,5-dimethyl-4-methoxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10733 D 7 3-(4-benzyloxy-3,5-dimethylbenzyl-idenyl)-5-methylaminosulfonyl- 2-indolinone 10733 D 83-(5-bromo-2-hydroxy-3-methoxy- benzylidenyl)-5-methylamino-sulfonyl-2-indolinone 10733 D 9 3-(5-bromo-2-hydroxybenzylidenyl)-5-methylaminosulfonyl-2- indolinone 10733 D 10 3-(2-hydroxy-5-nitrobenzylidenyl)- 5-methylaminosulfonyl-2-indolinone10733 D 11  3-(4-hydroxy-3-methoxy-2-nitro- benzylidenyl)-5-methylamino-sulfonyl-2-indolinone 10733 E 2 3-(4-benzyloxy-3-t-butyl-5-iodo-benzylidenyl)-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10733 E 3 3-(3-t-butyl-4-methoxy-5-nitro- benzylidenyl)-5-[4-(trifluoro-methyl)phenylaminosulfonyl]- 2-indolinone 10733 E 43-(3,5-di-t-butyl-4-methoxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl)-2-indolinone 10733 E 53-(4-benzyloxy-3,5-di-t-butylbenzyl- idenyl)-5-[4-(triflouromethyl)-phenylaminosulfonyl]-2-indolinone 10733 E 63-(3,5-dimethyl-4-methoxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl)-2-indolinone 10733 E 73-(4-benzyloxy-3,5-dimethylbenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10733 E 83-(5-bromo-2-hydroxy-3-methoxy- benzylidenyl)-5-[4-(trifluoro-methyl)phenylaminosulfonyl]-2- indolinone 10733 E 93-(5-bromo-2-hydroxybenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10733 E 10 3-(2-hydroxy-5-nitrobenzylidenyl)- 5-(4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10733 E 11  3-(4-hydroxy-3-methoxy-2-nitro-benzylidenyl)-5-[4-(trifluoro- methyl)phenylaminosulfonyl]- 2-indolinone10733 F 2 3-(4-benzyloxy-3-t-butyl-5-iodo-benzylidenyl)-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10733 F 33-(3-t-butyl-4-methoxy-5-nitro- benzylidenyl)-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10733 F 4 3-(3,5-di-t-butyl-4-methoxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10733 F 53-(4-benzyloxy-3,5-di-t-butylbenzyl- idenyl)-5-(morpholin-1-yl)sulfonyl-2-indolinone 10733 F 6 3-(3,5-dimethyl-4-methoxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10733 F 73-(4-benzyloxy-3,5-dimethylbenzyl- idenyl)-5-(morpholin-1-yl)sulfonyl-2-indolinone 10733 F 8 3-(5-bromo-2-hydroxy-3-methoxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10733 F 93-(5-bromo-2-hydroxybenzylidenyl)- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10733 F 10  3-(2-hydroxy-5-nitrobenzylidenyl)-5-(morpholin-1-yl)sulfonyl-2- indolinone 10733 F 11 3-(4-hydroxy-3-methoxy-2-nitro- benzylidenyl)-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10733 G 2 3-(4-benzyloxy-3-t-butyl-5-iodo-benzylidenyl)-5-(2-chloroethyl)- 2-indolinone 10733 G 33-(3-t-butyl-4-methoxy-5-nitro- benzylidenyl)-5-(2-chloroethyl)-2-indolinone 10733 G 4 3-(3,5-di-t-butyl-4-methoxybenzyl-idenyl)-5-(2-chloroethyl)-2- indolinone 10733 G 53-(4-benzyloxy-3,5-di-t-butylbenzyl- idenyl)-5-(2-chloroethyl)-2-indolinone 10733 G 6 3-(3,5-dimethyl-4-methoxybenzyl-idenyl)-5-(2-chloroethyl)-2- indolinone 10733 G 73-(4-benzyloxy-3,5-dimethylbenzyl- idenyl)-5-(2-chloroethyl)-2-indolinone 10733 G 8 3-(5-bromo-2-hydroxy-3-methoxy-benzylidenyl)-5-(2-chloroethyl)- 2-indolinone 10733 G 93-(5-bromo-2-hydroxybenzylidenyl)- 5-(2-chloroethyl)-2-indolinone 10733G 10  3-(2-hydroxy-5-nitrobenzylidenyl)- 5-(2-chloroethyl)-2-indolinone10733 G 11  3-(4-hydroxy-3-methoxy-2-nitro-benzylidenyl)-5-(2-chloroethyl)- 2-indolinone 10734 A 23-(3-ethoxy-2-hydroxybenzylidenyl)- 5,7-dibromo-2-indolinone 10734 A 33-(3,5-dichloro-2-hydroxybenzyl- idenyl)-5,7-dibromo-2-indolinone 10734A 4 3-(5-chloro-2-hydroxybenzyl- idenyl)-5,7-dibromo-2-indolinone 10734A 5 3-(4-diethylamino-2-hydroxybenzyl- idenyl)-5,7-dibromo-2-indolinone10734 A 6 3-(4-nitrobenzylidenyl)-5,7- dibromo-2-indolinone 10734 A 73-(3,5-dibromo-2-hydroxybenzyl- idenyl)-5,7-dibromo-2-indolinone 10734 A8 3-(3-fluoro-2-hydroxybenzylidenyl)- 5,7-dibromo-2-indolinone 10734 A 93-(3-bromo-4-hydroxybenzylidenyl)- 5,7-dibromo-2-indolinone 10734 A 10 3-(4-t-butylbenzylidenyl)-5,7- dibromo-2-indolinone 10734 A 11 3-[(2-bromothlen-5-yl)methyl- idenyl]-5,7-dibromo-2-indolinone 10734 B 23-(3-ethoxy-2-hydroxybenzylidenyl)- 5-iodo-2-indolinone 10734 B 33-(3,5-dichloro-2-hydroxybenzyl- idenyl)-5-iodo-2-indolinone 10734 B 43-(5-chloro-2-hydroxybenzylidenyl)- 5-iodo-2-indolinone 10734 B 53-(4-diethylamino-2-hydroxybenzyl- idenyl)-5-iodo-2-indolinone 10734 B 63-(4-nitrobenzylidenyl)-5-iodo- 2-indolinone 10734 B 73-(3,5-dibromo-2-hydroxybenzyl- idenyl)-5-iodo-2-indolinone 10734 B 83-(3-fluoro-2-hydroxybenzylidenyl)- 5-iodo-2-indolinone 10734 B 93-(3-bromo-4-hydroybenzylidenyl)- 5-iodo-2-indolinone 10734 B 10 3-(4-t-butylbenzylidenyl)-5-iodo- 2-indolinone 10734 B 11 3-[(2-bromothien-5-yl)methyl- idenyl]-5-iodo-2-indolinone 10734 C 23-(3-ethoxy-2-hydroxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10734C 3 3-(3,5-dichloro-2-hydroxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10734 C 4 3-(5-chloro-2-hydroxybenzylidenyl)-5-bromo-4-methyl-2-indolinone 10734 C 53-(4-diethylamino-2-hydroxybenzyl- idenyl)-5-bromo-4-methyl-2-indolinone 10734 C 6 3-(4-nitrobenzylidenyl)-5-bromo-4-methyl-2-indolinone 10734 C 7 3-(3,5-dibromo-2-hydroxybenzyl-idenyl)-5-bromo-4-methyl-2- indolinone 10734 C 83-(3-fluoro-2-hydroxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone 10734C 9 3-(3-bromo-4-hydroxybenzylidenyl)- 5-bromo-4-methyl-2-indolinone10734 C 10  3-(4-t-butylbenzylidenyl)-5-bromo- 4-methyl-2-indolinone10734 C 11  3-[(2-bromothien-5-yl)methyl- idenyl]-5-bromo-4-methyl-2-indolinone 10734 D 2 3-(3-ethoxy-2-hydroxybenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10734 D 33-(3,5-dichloro-2-hydroxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10734 D 4 3-(5-chloro-2-hydroxybenzylidenyl)-5-methylaminosulfonyl-2- indolinone 10734 D 53-(4-diethylamino-2-hydroxybenzyl- idenyl)-5-methylaminosulfonyl-2-indolinone 10734 D 6 3-(4-nitrobenzylidenyl)-5-methyl-aminosulfonyl-2-indolinone 10734 D 7 3-(3,5-dibromo-2-hydyoxybenzyl-idenyl)-5-methylaminosulfonyl- 2-indolinone 10734 D 83-(3-fluoro-2-hydroxybenzylidenyl)- 5-methylaminosulfonyl-2- indolinone10734 D 9 3-(3-bromo-4-hydroxybenzylidenyl)-5-methylaminosulfonyl-2-indolinone 10734 D 10 3-(4-t-butylbenzylidenyl)-5-methyl- aminosulfonyl-2-indolinone 10734 D11  3-[(2-bromothien-5-yl)methyl- idenyl]-5-methylaminosulfonyl-2-indolinone 10734 E 2 3-(3-ethoxy-2-hydroxybenzylidenyl)-5-[4-(trifluoromethyl)phenyl- aminosulfonyl-2-indolinone 10734 E 33-(3,5-dichloro-2-hydroxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2- indolinone 10734 E 43-(5-chloro-2-hydroxybenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl-2-indolinone 10734 E 5 3-(4-diethylamino-2-hydroxybenzyl-idenyl)-5-[4-(trifluoromethyl)- phenylaminosulfonyl]-2- indolinone 10734E 6 3-(4-nitrobenzylidenyl)-5-[4- (trifluoromethyl)phenylamino-sulfonyl]-2-indolinone 10734 E 7 3-(3,5-dibromo-2-hydroxybenzyl-idenyl)-5-[4-(trifluoromethyl)- phenylaminosulfonyl]-2- indolinone 10734E 8 3-(3-fluoro-2-hydroxybenzyl- idenyl)-5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2-indolinone 10734 E 93-(3-bromo-4hydroxybenzylidenyl)- 5-[4-(trifluoromethyl)phenyl-aminosulfonyl]-2-indolinone 10734 E 10  3-(4-t-butylbenzylidenyl)-5-[4-(trifluoromethyl)phenylamino- sulfonyl]-2-indolinone 10734 E 11 3-[(2-bromothien-5-yl)methyl- idenyl]5-[4-(trifluoromethyl)-phenylaminosulfonyl]-2- indolinone 10734 F 23-(3-ethoxy-2-hydroxybenzylidenyl)- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10734 F 3 3-(3,5-dichloro-2-hydroxybenzyl-idenyl)-5-(morpholin-1-yl)- sulfonyl-2-indolinone 10734 F 43-(5-chloro-2-hydroxybenzyl- idenyl)-5-(morpholin-1-yl)-sulfonyl-2-indolinone 10734 F 5 3-(4-diethylamino-2-hydroxybenzyl-idenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10734 F 63-(4-nitrobenzylidenyl)-5-(morpholin- 1-yl)sulfonyl-2-indolinone 10734 F7 3-(3,5-dibromo-2-hydroxybenzyl- idenyl)-5-(morpholin-1-yl)sulfonyl-2-indolinone 10734 F 8 3-(3-fluoro-2-hydroxybenzylidenyl)-5-(morpholin-1-yl)sulfonyl- 2-indolinone 10734 F 93-(3-bromo-4-hydroxybenzylidenyl)- 5-(morpholin-1-yl)sulfonyl-2-indolinone 10734 F 10  3-(4-t-butylbenzylidenyl)-5-(morpholin-1-yl)sulfonyl-2- indolinone 10734 F 11  10734 G 23-(3-ethoxy-2-hydroxybenzylidenyl)- 5-(2-chloroethyl)-2-indolinone 10734G 3 3-(3,5-dichloro-2-hydroxybenzyl- idenyl)-5-(2-chloroethyl)-2-indolinone 10734 G 4 3-(5-chloro-2-hydroxybenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10734 G 53-(4-diethylamino-2-hydroxybenzyl- idenyl)-5-(2-chloroethyl)-2-indolinone 10734 G 6 3-(4-nitrobenzylidenyl)-5-(2-chloroethyl-2-indolinone 10734 G 7 3-(3,5-dibromo-2-hydroxybenzyl-idenyl)-5-(2-chloroethyl)-2- indolinone 10734 G 83-(3-fluoro-2-hydroxybenzyl- idenyl)-5-(2-chloroethyl)-2- indolinone10734 G 9 3-(3-bromo-4-hydroxybenzylidenyl)-5-(2-chloroethyl)-2-indolinone 10734 G 10 3-(4-t-butylbenzylidenyl)-5-(2- chloroethyl)-2-indolinone 10734 G 11 3-[(2-bromothien-5-yl)methylidenyl]- 5-(2-chloroethyl)-2-indolinone

[0622] TABLE 14 Barcode/ Biochem PDGF Plate Row- Flk Kinase EGFR KinaseMet Kinase Plate Column % Inhibition % Inhibition % Inhibition %Inhibition 10717/A02 0.1 24.3 46.1 10717/A03 2.9 1.0 54.6 10717/A04 −4.529.0 37.4 10717/A05 −2.6 16.6 35.6 10717/A06 −10.8 −7.8 31.7 10717/A07−6.4 20.2 29.2 10717/A08 −5.2 39.1 21.7 10717/A09 −3.9 37.7 9.410717/A10 −3.3 8.1 71.6 10717/A11 −5.8 59.9 64.8 10717/B02 5.0 31.7 87.510717/B03 −8.8 7.3 90.5 10717/B04 −18.3 10.3 70.0 10717/B05 1.0 31.787.4 10717/B06 5.4 −30.8 89.5 10717/B07 −18.3 58.3 90.0 10717/B08 −0.960.5 88.8 10717/B09 −40.7 78.3 88.8 10717/B10 −2.3 16.1 56.1 10717/B1111.4 82.7 91.0 10717/C02 4.1 −0.4 29.7 10717/C03 −7.7 18.0 25.310717/C04 −0.8 14.4 25.0 10717/C05 −2.3 13.1 44.6 10717/C06 7.6 −49.744.1 10717/C07 1.6 28.7 16.5 10717/C08 7.0 24.3 27.3 10717/C09 77.1 8.147.7 10717/C10 −8.0 17.5 22.8 10717/C11 4.6 67.3 71.8 10717/D02 5.1 10.128.6 10717/D03 1.1 −1.4 11.1 10717/D04 −2.1 4.9 21.0 10717/D05 −3.8 −2.823.8 10717/D06 1.0 −23.4 33.8 10717/D07 −8.4 −4.5 16.8 10717/D08 6.8−7.8 16.0 10717/D09 −55.0 6.8 29.1 10717/D10 -6.0 3.5 15.6 10717/D1111.6 59.1 55.3 10717/E02 17.9 17.2 24.0 10717/E03 19.0 11.7 52.210717/E04 6.1 −28.3 29.4 10717/E05 13.2 22.4 39.1 10717/E06 7.5 −26.124.8 10717/E07 15.3 −7.8 41.0 10717/E08 13.2 28.2 51.7 10717/E09 −1.1−5.8 19.2 10717/E10 4.7 −6.1 35.9 10717/E11 8.9 44.9 75.1 10717/F02 2.26.2 30.4 10717/F03 0.5 −4.7 42.8 10717/F04 −0.1 −15.7 11.4 10717/F05 3.2−20.1 21.5 10717/F06 8.9 −22.8 49.0 10717/F07 2.0 −14.3 37.6 10717/F08−0.7 −23.4 64.0 10717/F09 −13.3 1.8 41.4 10717/F10 −4.4 −26.4 54.610717/F11 1.4 91.2 81.5 10717/G02 14.9 32.3 30.7 10717/G03 1.8 18.8 4.510717/G04 0.8 6.0 10.9 10717/G05 5.3 −0.1 4.7 10717/G06 4.3 −3.4 34.010717/G07 −17.0 13.1 7.5 10717/G08 1.9 36.4 10.9 10717/G09 −29.7 24.919.1 10717/G10 4.8 2.4 30.9 10717/G11 16.4 71.7 73.8 10718/A02 3.0 11.354.6 10718/A03 7.6 −6.1 92.7 10718/A04 6.9 27.3 81.7 10718/A05 3.2 −6.936.1 10718/A06 7.8 19.4 61.3 10718/A07 16.2 −10.6 58.6 10718/A08 3.2 5.836.8 10718/A09 −18.4 −4.1 67.7 10718/A10 23.4 41.5 77.9 10718/A11 2.721.2 58.9 10718/B02 7.0 24.9 52.9 10718/B03 1.7 −0.2 77.9 10718/B04 11.88.5 63.9 10718/B05 11.5 56.3 76.0 10718/B06 16.5 28.5 78.4 10718/B0717.7 9.9 53.7 10718/B08 5.4 28.9 63.4 10718/809 −14.7 −0.8 52.910718/B10 20.1 13.7 83.6 10718/B11 4.5 30.3 69.6 10718/C02 26.2 −21.929.6 10718/C03 −13.9 41.3 95.7 10718/C04 15.3 14.8 93.1 10718/C05 20.510.9 8.7 10718/C06 16.8 5.6 3.9 10718/C07 6.3 −4.9 29.6 10718/C08 19.613.1 22.7 10718/C09 5.3 26.5 38.2 10718/C10 −11.9 −18.7 4.4 10718/C1111.4 −0.2 10.1 10718/D02 13.3 14.4 32.0 10718/D03 1.1 61.9 92.910718/D04 6.4 52.0 92.9 10718/D05 11.5 2.8 10.6 10718/D06 15.8 20.0 11.110718/D07 7.8 5.6 26.1 10718/D08 3.9 3.0 2.3 10718/D09 −9.1 6.0 9.910718/D10 15.0 12.3 55.3 10718/D11 13.3 5.4 11.3 10718/E02 19.7 1.0 46.310718/E03 10.0 50.4 95.3 10718/E04 15.1 16.4 87.7 10718/E05 16.1 −3.132.2 10718/E06 15.4 2.0 33.4 10718/E07 15.6 13.9 80.5 10718/E08 9.2 9.369.6 10718/E09 0.9 17.0 80.8 10718/E10 15.2 −7.5 60.8 10718/E11 12.1−15.2 37.5 10718/F02 20.1 17.8 66.7 10718/F03 −0.2 22.5 87.9 10718/F049.4 1.2 78.1 10718/F05 19.5 −4.9 53.7 10718/F06 18.3 −9.1 42.5 10718/F0716.5 −6.3 67.9 107181F08 15.3 −8.7 28.4 10718/F09 −3.0 −9.5 52.710718/F10 17.9 −12.0 23.7 10718/F11 10.1 −3.9 31.3 10718/G02 −2.5 49.267.7 10718/G03 −4.7 57.3 77.9 10718/G04 1.8 15.8 78.1 10718/G05 3.7 2.860.3 10718/G06 9.8 −18.7 61.0 10718/G07 11.4 −21.3 52.0 10718/G08 6.1−8.3 17.5 10718/G09 −12.8 −15.4 27.0 10718/G10 7.1 −7.5 10.8 10718/G1115.6 −4.9 3.0 10719/A02 21.4 43.0 40.9 10719/A03 3.9 67.7 84.1 10719/A0419.2 43.7 22.9 10719/A05 10.0 23.1 39.6 10719/A06 14.0 18.2 −7.010719/A07 21.3 15.5 68.1 10719/A08 11.9 47.3 75.5 10719/A09 12.3 2.247.0 10719/A10 10.9 8.2 13.4 10719/A11 7.4 10.5 34.9 10719/B02 11.5 29.047.0 10719/B03 14.2 59.5 85.8 10719/B04 24.9 29.9 38.4 10719/B05 17.735.9 33.6 10719/B06 21.3 −0.5 22.5 10719/B07 12.5 23.7 52.2 10719/B084.0 42.3 33.2 10719/B09 11.3 −17.7 23.5 10719/B10 1.1 −1.2 53.410719/B11 11.2 −23.9 36.5 10719/C02 4.1 10.2 41.3 10719/C03 15.3 60.669.1 10719/C04 59.9 14.4 14.7 10719/C05 25.6 27.4 35.5 10719/C06 47.7−14.3 18.4 10719/C07 31.2 14.4 7.7 10719/C08 15.0 −10.2 57.5 10719/C0923.5 −0.1 8.9 10719/C10 11.8 10.7 7.9 10719/C11 9.9 −25.7 −5.1 10719/D029.7 9.8 27.5 10719/D03 4.8 95.7 93.2 10719/D04 27.8 15.3 28.9 10719/D0516.3 18.5 71.8 10719/D06 25.8 −12.2 11.2 10719/D07 −123.5 13.7 41.510719/D08 8.2 −12.2 45.2 10719/D09 7.8 −3.1 13.0 10719/D10 8.3 −11.822.3 10719/D11 −8.7 −11.1 12.8 10719/E02 26.1 40.0 35.7 10719/E03 17.173.0 87.2 10719/E04 31.2 −7.4 3.1 10719/E05 21.5 21.2 39.0 10719/E0617.1 −42.0 −4.5 10719/E07 26.7 −18.4 55.5 10719/E08 21.8 36.8 80.010719/E09 13.5 −33.1 36.1 10719/E10 17.6 −32.4 40.2 10719/E11 26.3 −51.828.5 10719/F02 28.6 14.8 28.1 10719/F03 11.2 −30.8 89.5 10719/F04 26.6−6.0 3.3 10719/F05 20.7 35.0 63.1 10719/F06 13.5 −26.0 −22.0 10719/F0718.7 20.1 36.7 10719/F08 15.1 90.9 75.7 10719/F09 −6.5 −17.7 19.210719/F10 10.4 −17.7 30.8 10719/F11 11.6 −66.3 8.7 10719/G02 27.3 −12.2−2.4 10719/G03 −25.8 89.5 87.6 10719/G04 11.5 −4.7 −8.2 10719/G05 18.04.0 15.9 10719/G06 23.2 −45.7 −18.1 10719/G07 20.1 −8.1 24.0 10719/G083.2 65.4 39.4 10719/G09 18.1 −32.8 1.3 10719/G10 9.7 −27.6 35.510719/G11 6.9 −44.1 24.0 10720/A02 4.7 11.3 45.2 10720/A03 17.7 −5.358.2 10720/A04 12.3 −1.8 62.3 10720/A05 8.0 −4.4 43.4 10720/A06 5.6 44.763.6 10720/A07 6.6 42.5 57.2 10720/A08 −2.2 −23.2 77.9 10720/A09 8.1 8.675.4 10720/A10 −5.2 −2.7 68.4 10720/A11 −0.6 −23.2 58.7 10720/B02 6.518.4 38.8 10720/B03 6.4 32.3 53.3 10720/B04 9.8 50.5 61.8 10720/B05 11.658.4 51.8 10720/B06 7.3 21.2 55.1 10720/B07 12.0 52.0 61.5 10720/B08 3.6−12.6 27.7 10720/B09 10.1 37.6 57.4 10720/B10 −5.5 50.2 45.2 10720/B11−20.3 22.4 42.1 10720/C02 18.0 23.5 63.6 10720/C03 15.1 0.9 50.310720/C04 15.3 −13.1 29.0 10720/C05 −36.1 −15.3 72.5 10720/C06 12.2 −9.736.7 10720/C07 20.7 −25.4 26.7 10720/C08 10.9 −1.1 65.6 10720/C09 12.144.7 47.5 10720/C10 −21.1 2.0 62.6 10720/C11 52.5 −21.9 30.0 10720/D0212.1 11.1 17.8 10720/D03 17.0 0.9 61.5 10720/D04 15.6 −7.7 23.610720/D05 4.8 −24.1 9.8 10720/D06 10.1 −35.0 31.8 10720/D07 11.8 14.836.2 10720/D08 3.3 −13.3 42.1 10720/D09 5.8 2.4 62.8 10720/D10 −6.6−10.2 51.0 10720/D11 9.8 −5.5 23.9 10720/E02 5.7 25.2 18.0 10720/E0334.3 54.4 54.9 10720/E04 18.4 −2.7 46.7 10720/E05 −13.8 40.7 55.410720/E06 25.5 30.1 33.1 10720/E07 18.8 55.1 30.3 10720/E08 2.5 37.455.1 10720/E09 11.5 56.4 43.4 10720/E10 −4.1 49.1 23.1 10720/E11 9.3−65.5 −10.4 10720/F02 9.1 −19.3 17.8 10720/F03 10.6 7.1 44.1 10720/F0410.6 −11.7 43.1 10720/F05 −3.6 −14.2 39.8 10720/F06 11.9 −24.3 21.910720/F07 4.6 35.2 64.6 10720/F08 −4.1 −39.6 36.2 10720/F09 5.9 6.4 49.210720/F10 −2.6 6.0 42.8 10720/F11 5.0 −61.1 1.6 10720/G02 5.0 −13.1 20.110720/G03 2.6 10.0 42.1 10720/G04 2.4 −34.1 5.0 10720/G05 −2.9 27.0 37.010720/G06 −3.4 −10.4 21.6 10720/G07 5.1 −8.0 12.9 10720/G08 −17.9 −9.526.7 10720/G09 2.1 −19.7 49.5 10720/G10 −36.6 20.4 55.9 10720/G11 −18.0−56.7 36.2 10721/A02 10.6 17.8 41.1 10721/A03 11.4 25.5 56.2 10721/A046.5 59.0 85.0 10721/A05 12.5 41.4 52.9 10721/A06 6.4 32.7 81.3 10721/A07−4.7 35.2 29.7 10721/A08 4.8 24.0 29.9 10721/A09 10.9 28.0 23.010721/A10 5.2 31.1 68.9 10721/A11 4.8 24.6 23.9 10721/B02 19.5 58.6 82.610721/B03 19.9 38.9 70.8 10721/B04 13.8 79.3 93.1 10721/B05 45.9 76.870.8 10721/B06 3.4 71.5 92.4 10721/B07 11.2 47.6 47.1 10721/B08 18.564.0 64.5 10721/B09 9.0 38.9 28.3 10721/B10 20.9 42.9 30.4 10721/B11−2.1 34.6 6.7 10721/C02 9.7 68.3 59.2 10721/C03 16.5 64.6 6.2 10721/C0421.8 77.7 88.7 10721/C05 56.4 68.1 48.7 10721/C06 14.4 80.2 56.410721/C07 10.9 24.6 25.7 10721/C08 55.8 38.3 24.8 10721/C09 17.5 39.8−4.7 10721/C10 21.1 17.4 44.6 10721/C11 13.9 14.1 3.7 10721/D02 15.121.5 22.5 10721/D03 17.8 11.6 19.5 10721/D04 15.2 5.0 35.3 10721/D05−25.1 47.0 91.9 10721/D06 1.6 44.5 9.0 10721/D07 6.4 23.0 −6.8 10721/D083.9 31.7 45.3 10721/D09 17.6 15.3 −4.9 10721/D10 23.7 3.3 13.4 10721/D1120.6 22.2 23.2 10721/E02 17.2 −9.5 38.8 10721/E03 10.9 25.1 12.310721/E04 16.0 48.5 87.3 10721/E05 10.8 61.3 69.9 10721/E06 40.4 91.581.0 10721/E07 15.6 37.7 43.6 10721/E08 15.7 29.8 39.5 10721/E09 36.942.5 0.7 10721/E10 9.3 19.9 55.7 10721/E11 0.7 32.1 31.3 10721/F02 17.011.0 27.8 10721/F03 9.1 7.0 40.6 10721/F04 7.4 0.0 26.0 10721/F05 8.120.5 67.8 10721/F06 2.2 21.7 80.3 10721/F07 4.8 3.5 55.7 10721/F08 −6.437.3 76.1 10721/F09 65.2 7.0 52.5 10721/F10 49.6 7.5 79.9 10721/F11 29.795.9 78.2 10721/G02 16.4 23.6 7.9 10721/G03 12.1 23.4 25.3 10721/G04 3.264.6 90.3 10721/G05 −15.1 7.7 8.6 10721/G06 18.9 23.2 39.5 10721/G07 3.314.7 10.0 10721/G08 5.4 12.8 −2.4 10721/G09 20.4 14.9 5.1 10721/G10 24.42.1 12.0 10721/G11 −7.1 0.4 −0.0 10722/A02 0.8 23.7 28.9 44.9 10722/A036.7 0.8 29.5 90.3 10722/A04 13.4 21.0 −0.9 51.4 10722/A05 10.5 22.4 33.590.5 10722/A06 9.6 28.4 19.8 71.6 10722/A07 9.4 29.9 23.8 64.1 10722/A0813.7 23.9 15.2 70.5 10722/A09 7.3 16.8 21.5 86.5 10722/A10 6.6 −4.2 15.279.0 10722/A11 6.7 −0.1 21.5 68.6 10722/B02 10.1 16.3 28.9 44.310722/B03 13.8 19.6 3.7 40.1 10722/B04 14.7 10.6 3.1 53.4 10722/B05 18.59.3 21.5 67.2 10722/B06 13.9 −4.9 21.5 72.6 10722/B07 6.6 6.2 20.9 48.210722/B08 11.2 0.5 27.8 72.0 10722/B09 8.7 7.8 14.6 59.7 10722/B10 −0.9−11.3 20.3 56.4 10722/B11 5.2 −15.5 25.5 83.0 10722/C02 29.1 32.1 30.634.5 10722/C03 16.7 42.3 22.6 73.6 10722/C04 10.7 26.7 8.9 70.710722/C05 23.5 19.1 26.6 44.9 10722/C06 24.5 −11.0 24.9 45.1 10722/C0715.8 −15.5 31.2 61.2 10722/C08 17.8 14.8 31.2 80.1 10722/C09 25.9 −3.132.4 45.1 10722/C10 2.3 22.8 18.0 33.9 10722/C11 13.8 −14.2 36.4 52.610722/D02 30.7 26.1 31.8 26.4 10722/D03 15.0 31.0 −9.4 52.8 10722/D0423.5 20.3 15.7 63.4 10722/D05 21.4 −3.8 22.0 35.8 10722/D06 21.9 −2.58.9 32.4 10722/D07 14.1 −2.8 25.5 42.6 10722/D08 29.1 −2.6 41.5 60.510722/D09 14.7 −17.2 30.6 52.2 10722/D10 8.2 −0.6 41.5 40.5 10722/D119.6 −10.1 15.2 41.0 10722/E02 17.0 22.2 23.2 71.1 10722/E03 10.7 33.0−7.2 88.4 10722/E04 38.6 1.4 30.6 52.6 10722/E05 19.2 −7.0 19.2 73.010722/E06 21.4 7.6 32.9 71.6 10722/E07 24.3 28.7 40.9 71.6 10722/E0818.6 10.4 38.7 82.8 10722/E09 16.2 4.1 26.6 55.1 10722/E10 3.1 −13.331.8 86.6 10722/E11 15.3 4.2 28.3 84.0 10722/F02 5.3 9.2 12.9 33.910722/F03 12.0 13.7 −14.0 59.7 10722/F04 27.5 16.8 −2.0 58.9 10722/F0515.0 −2.8 6.0 6.4 10722/F06 11.0 6.5 2.6 6.0 10722/F07 15.5 −3.7 −6.663.0 10722/F08 66.3 −5.4 25.5 89.3 10722/F09 15.3 −35.8 26.6 65.710722/F10 3.3 10.7 24.9 67.8 10722/F11 4.5 −6.5 15.7 73.2 10722/G02 15.127.3 14.6 43.0 10722/G03 5.3 4.1 −3.7 52.2 10722/G04 7.2 −13.3 11.7 63.210722/G05 10.8 −9.0 −6.0 9.7 10722/G06 7.4 −5.2 −6.0 12.2 10722/G07 8.0−32.5 −3.7 41.2 10722/G08 8.2 −8.5 12.9 66.1 10722/G09 6.1 −5.9 0.9 51.010722/G10 −1.7 3.3 16.9 27.0 10722/G11 0.6 −39.4 0.3 35.3 10723/A02 −5.597.8 64.4 100.8 10723/A03 1.2 38.5 11.7 76.5 10723/A04 27.2 30.8 13.197.9 10723/A05 −17.8 26.4 17.9 75.7 10723/A06 8.6 20.1 43.6 79.110723/A07 −6.1 3.9 22.1 63.2 10723/A08 −12.9 −2.1 29.7 77.3 10723/A09−1.0 −4.5 42.9 85.9 10723/A10 −3.1 −24.8 34.6 62.1 10723/A11 42.9 −4.041.5 60.0 10723/B02 −0.3 91.0 29.0 100.3 10723/B03 7.1 −5.0 14.5 82.510723/B04 18.7 5.1 40.1 90.6 10723/B05 −15.4 36.4 15.2 85.1 10723/B0631.8 11.9 58.8 90.6 10723/B07 6.5 28.8 24.9 86.7 10723/B08 1.0 −0.4 56.182.8 10723/B09 2.7 −12.0 27.6 57.7 10723/B10 5.8 1.8 17.2 88.5 10723/B116.3 −26.0 22.8 62.6 10723/C02 9.6 73.6 39.4 100.6 10723/C03 −3.1 5.942.9 88.8 10723/C04 8.8 23.5 36.7 91.9 10723/C05 5.6 35.2 22.8 73.110723/C06 17.8 −4.5 26.3 63.4 10723/C07 20.9 −4.0 27.6 44.3 10723/C08−35.5 45.0 29.0 83.0 10723/C09 −22.3 62.7 62.3 84.6 10723/C10 9.5 −7.225.6 43.8 10723/C11 9.5 −1.1 8.9 47.0 10723/D02 2.0 63.2 22.1 93.010723/D03 −14.7 33.5 8.2 69.4 10723/D04 15.2 45.1 31.8 97.7 10723/D05−6.1 3.7 8.2 54.5 10723/D06 17.6 −7.4 6.2 60.0 10723/D07 15.8 13.4 16.621.9 10723/D08 −4.5 4.9 31.1 53.5 10723/D09 50.4 −3.8 21.4 62.610723/D10 6.5 −9.3 21.4 38.1 10723/D11 14.8 −6.2 24.9 42.0 10723/E02 8.191.0 46.4 97.9 10723/E03 8.7 8.3 47.1 76.8 10723/E04 30.7 59.8 36.0 94.510723/E05 8.9 −15.6 −4.9 63.7 10723/E06 19.3 11.5 18.6 74.4 10723/E0717.4 38.1 14.5 47.7 10723/E08 −0.4 52.6 26.3 89.3 10723/E09 7.9 29.122.1 91.7 10723/E10 5.2 −7.9 44.3 59.5 10723/E11 8.9 −44.6 32.5 50.110723/F02 10.3 70.4 1.3 99.0 10723/F03 4.4 9.3 1.3 78.3 10723/F04 12.317.5 21.4 94.0 10723/F05 −6.4 −3.8 −7.7 45.6 10723/F06 20.4 5.4 −30.684.1 10723/F07 20.7 −4.1 6.8 26.6 10723/F08 −0.5 5.7 20.7 75.5 10723/F091.2 14.1 3.4 78.6 10723/F10 9.1 4.2 −2.2 74.1 10723/F11 −1.2 −41.3 36.772.3 10723/G02 −1.6 90.8 13.8 99.2 10723/G03 4.3 18.5 6.2 74.7 10723/G048.7 16.7 21.4 85.9 10723/G05 −9.4 1.3 2.0 79.9 10723/G06 14.1 −26.7 −0.864.5 10723/G07 14.2 15.5 −5.6 43.0 10723/G08 −22.9 0.1 7.5 79.910723/G09 −1.8 −32.6 −2.9 80.7 10723/G10 3.5 −4.1 −27.8 40.7 10723/G11−4.1 −35.0 −7.7 39.4 10724/A02 1.8 36.7 6.3 61.7 10724/A03 −7.8 17.2 0.130.7 10724/A04 −15.9 15.4 5.0 62.6 10724/A05 −15.2 20.3 5.0 68.410724/A06 −3.7 1.4 30.7 46.8 10724/A07 3.7 18.3 16.1 58.7 10724/A09 −5.21.6 19.6 37.5 10724/A10 1.6 40.0 28.6 83.8 10724/A11 12.8 −16.6 29.327.2 10724/B02 −6.2 34.9 −21.5 48.8 10724/B03 −48.9 14.9 14.7 51.010724/B04 −20.5 50.2 42.5 81.2 10724/B05 −2.2 21.2 12.6 45.6 10724/B0613.4 30.9 43.2 52.1 10724/B07 −1.8 44.0 27.2 57.9 10724/B09 3.5 8.7 25.843.8 10724/B10 8.5 76.2 9.8 95.0 10724/B11 9.0 −23.2 23.0 43.0 10724/C02−0.3 53.6 −9.0 40.7 10724/C03 −20.3 16.5 4.3 68.7 10724/C04 −18.6 13.224.4 84.3 10724/C05 −18.6 −0.8 20.3 67.7 10724/C06 −1.5 −2.4 34.9 15.410724/C07 −1.2 9.4 22.3 14.2 10724/C09 9.3 1.0 20.3 5.3 10724/C10 −2.313.8 27.2 91.2 10724/C11 10.3 0.7 23.0 4.9 10724/D02 12.4 40.5 −9.6 37.510724/D03 0.1 2.5 −15.2 18.2 10724/D04 0.5 5.4 −1.3 70.5 10724/D05 −1.6−8.4 35.6 36.1 10724/D06 12.4 −12.4 40.4 23.0 10724/D07 −2.6 25.6 7.038.1 10724/D09 0.9 −15.3 18.9 16.1 10724/D10 3.7 12.7 38.3 59.610724/D11 14.9 12.9 29.3 20.3 10724/E02 17.7 39.8 −54.2 55.4 10724/E0310.6 33.1 14.7 85.8 10724/E04 55.2 8.9 −32.6 93.3 10724/E05 13.8 0.5−7.6 70.3 10724/E06 8.3 1.6 6.3 25.8 10724/E07 −3.6 9.4 0.1 46.810724/E09 14.3 6.3 21.0 27.0 10724/E10 7.3 41.4 34.9 84.0 10724/E11 5.1−26.8 5.0 39.3 10724/F02 9.7 27.4 0.8 73.0 10724/F03 −12.5 9.8 −45.844.2 10724/F04 10.2 2.9 −52.1 81.9 10724/F05 −7.2 −16.4 −0.6 67.010724/F06 13.8 −3.5 −5.5 51.2 10724/F07 −6.0 8.9 −6.2 47.3 10724/F0917.1 −14.6 −17.3 20.5 10724/F10 2.7 −10.4 1.5 55.6 10724/F11 4.5 3.8−6.9 49.3 10724/G02 15.1 42.5 −7.6 44.9 10724/G03 −8.4 7.8 −2.7 36.710724/G04 −7.9 12.9 −12.4 71.0 10724/G05 −0.1 −20.8 −10.3 61.0 10724/G060.1 3.2 −6.9 20.3 10724/G07 −1.9 −11.7 −41.6 2.3 10724/G09 9.1 −21.7−18.0 −2.8 10724/G10 7.0 −10.6 −15.9 62.8 10724/G11 6.8 −29.5 −29.1 11.210725/A02 −2.0 3.9 −14.2 46.6 10725/A03 3.6 −38.2 5.9 68.0 10725/A04−8.6 26.2 −3.2 55.3 10725/A05 −13.9 7.9 13.1 47.5 10725/A06 −7.3 −9.540.9 71.7 10725/A07 −12.3 18.2 17.9 59.3 10725/A08 −2.9 10.9 14.1 45.310725/A09 −13.9 4.9 29.4 44.3 10725/A10 −3.2 14.0 33.7 43.2 10725/A11−21.9 14.6 18.9 49.1 10725/B02 −2.8 2.5 −7.5 66.9 10725/B03 4.9 −15.37.8 70.8 10725/B04 1.1 76.9 9.3 90.4 10725/B04 −61.0 20.4 44.7 68.310725/B06 −0.5 −13.7 31.3 53.3 10725/B07 24.6 45.8 100.8 74.0 10725/B08−24.1 41.8 29.4 66.7 10725/B09 0.4 72.3 43.8 65.7 10725/B10 5.1 53.326.0 69.9 10725/B11 −42.3 43.0 66.3 76.3 10725/C02 7.0 −43.4 −5.1 6.310725/C03 2.0 −12.7 19.3 72.9 10725/C04 −27.3 31.8 25.1 75.9 10725/C05−37.0 −21.9 28.9 31.7 10725/C06 −9.3 −11.5 46.6 54.7 10725/C07 65.0−16.5 107.0 38.8 10725/C08 −8.7 −11.9 101.7 28.0 10725/C09 11.2 23.634.7 24.1 10725/C10 8.7 5.3 38.5 −0.6 10725/C11 104.5 −22.1 80.7 48.410725/D02 −3.6 −23.9 −8.4 14.0 10725/D03 −11.3 −2.5 5.4 72.9 10725/D043.6 4.3 12.2 55.1 10725/D05 2.3 19.7 10.7 24.5 10725/D06 −0.5 −26.4 21.724.7 10725/D07 2.6 −25.8 18.4 37.0 10725/D08 1.8 20.0 38.5 39.210725/D09 −0.9 4.3 35.6 28.0 10725/D10 9.0 11.7 43.8 27.8 10725/D11 13.6−12.5 23.2 100.5 10725/E02 −5.6 4.3 −8.9 40.2 10725/E03 −0.8 −10.3 10.760.9 10725/E04 −38.8 31.2 3.1 59.0 10725/E05 −0.2 −5.5 27.5 28.210725/E06 −1.8 −17.7 39.0 36.7 10725/E07 9.7 12.5 28.9 45.3 10725/E0812.1 14.2 48.6 39.7 10725/E09 7.0 31.4 37.5 22.4 10725/E10 9.3 6.1 28.4−4.7 10725/E11 18.9 −36.0 20.8 9.6 10725/F02 5.8 −3.7 −15.1 27.810725/F03 4.3 −36.2 −27.1 63.2 10725/F04 −6.9 −49.6 −4.6 38.1 10725/F05−0.8 −18.9 −5.6 15.5 10725/F06 −1.0 −37.8 14.1 41.8 10725/F07 6.9 16.415.0 67.8 10725/F08 8.9 15.4 28.9 72.2 10725/F09 6.8 32.2 28.4 48.510725/F10 4.8 3.7 17.9 14.2 10725/F11 9.9 20.8 20.3 25.7 10725/G02 −3.7−20.5 −11.8 30.8 10725/G03 −6.9 −2.5 −6.5 58.6 10725/G04 6.1 −12.3 −8.947.1 10725/G05 −18.3 68.7 7.4 15.6 10725/G06 21.7 −19.9 27.5 35.810725/G07 4.8 −25.8 23.7 39.7 10725/G08 −14.8 −13.7 8.3 47.3 10725/G0915.2 6.5 43.8 4.7 10725/G10 11.1 17.8 44.7 27.7 10725/G11 −28.0 −32.422.2 25.7 10726/A03 −2.6 −12.5 4.3 70.1 10726/A04 7.6 40.8 44.2 85.710726/A05 −7.1 −28.4 22.1 75.2 10726/A06 −4.6 0.2 22.1 54.7 10726/A07−72.3 88.7 −36.8 101.4 10726/A08 −4.0 −28.4 10.7 63.1 10726/A09 −4.5−6.3 16.4 70.8 10726/A10 3.7 26.5 8.1 58.9 10726/A11 0.5 6.2 23.3 70.810725/B03 11.1 3.5 16.4 81.1 10726/B04 16.8 71.1 39.1 78.9 10726/B0513.2 49.0 27.1 96.8 10726/B06 11.3 6.6 34.1 76.1 10726/B07 −36.5 72.4−59.5 98.5 10726/B08 12.2 23.6 24.6 60.2 10726/B09 7.5 28.9 22.7 72.310726/B10 3.7 40.8 6.2 58.5 10726/B11 7.4 39.4 23.3 64.4 10726/C03 24.929.8 28.4 38.9 10726/C04 12.3 58.4 36.6 91.7 10726/C05 4.0 16.7 25.258.0 10726/C06 23.8 −0.9 36.0 42.6 10726/C07 −17.0 40.8 −67.7 84.910726/C08 3.4 7.5 21.4 46.8 10726/C09 12.9 −14.3 26.5 48.5 10726/C10 5.52.8 16.4 36.7 10726/C11 −32.2 4.8 51.1 34.7 10726/D03 21.6 −5.4 21.452.1 10726/D04 7.8 −20.1 34.1 62.9 10726/D05 8.2 −8.1 39.1 51.210726/D05 16.3 −24.4 28.4 42.8 10726/D07 −26.9 18.5 −81.0 84.6 10726/D0812.1 −11.4 22.1 39.5 10726/D09 14.4 −6.5 22.1 45.7 10726/D10 14.7 −6.532.2 35.3 10726/D11 10.5 −6.3 30.9 9.6 10726/E03 −5.5 −15.9 20.2 62.410726/E04 8.1 53.0 12.6 85.5 10726/E05 8.1 5.5 4.3 71.0 10726/E06 6.2−20.6 41.7 −7.4 10726/E07 −40.0 20.5 −12.1 84.0 10726/E08 4.1 −8.5 34.158.9 10726/E09 9.9 10.0 34.7 50.3 10726/E10 16.5 −9.0 37.9 41.510726/E11 16.2 −14.1 30.3 34.5 10726/F03 8.3 −17.4 5.6 54.1 10726/F0431.5 33.4 18.3 93.5 10726/F05 8.9 −26.8 −17.8 51.2 10726/F06 17.7 −24.117.0 16.2 10726/F07 9.6 76.2 −99.4 96.1 10726/F08 15.3 −21.5 28.4 67.310726/F09 9.6 −22.8 −2.6 66.8 10726/F10 7.0 −17.4 9.4 51.4 10726/F1113.6 −16.8 25.2 57.6 10726/G03 11.3 −17.2 4.3 26.8 10726/G04 9.7 60.614.5 72.8 10726/G05 14.9 5.1 6.2 81.1 10726/G06 7.0 −37.5 −26.6 19.910726/G07 −13.7 54.4 −107.6 94.8 10726/G08 2.9 −2.7 14.5 39.1 10726/G093.6 3.3 13.2 42.4 10726/G10 10.5 6.0 −7.0 26.8 10726/G11 9.1 1.3 −7.711.8 10727/A02 −1.3 3.2 −10.3 52.0 10727/A03 6.3 −19.2 −4.5 40.710727/A04 −4.6 28.2 12.3 80.9 10727/A05 4.2 −3.0 5.7 29.0 10727/A06−17.1 −6.3 13.7 32.7 10727/A07 −10.7 −3.7 12.3 61.1 10727/A08 −0.6 9.715.2 9.7 10727/A09 −16.8 12.7 16.6 44.2 10727/A10 −6.4 89.0 18.1 95.210727/A11 7.4 6.2 10.8 16.5 10727/B02 2.4 −18.4 −10.3 90.5 10727/B03−13.4 −2.8 −7.4 84.5 10727/B04 46.0 47.4 21.0 87.1 10727/B05 10.5 39.09.4 83.3 10727/B06 −3.9 40.7 6.4 91.0 10727/B07 8.4 46.5 0.6 83.510727/B08 4.0 47.4 14.4 90.7 10727/B09 6.7 31.7 18.1 81.9 10727/B10 3.994.0 29.7 99.2 10727/B11 16.8 6.9 15.9 69.8 10727/C02 −2.0 −28.5 −12.573.8 10727/C03 −3.2 14.6 11.5 11.9 10727/C04 0.2 27.6 23.2 81.710727/C05 13.7 11.8 7.9 8.9 10727/C06 5.2 5.6 12.3 45.2 10727/C07 15.98.4 13.0 36.7 10727/C08 4.9 3.6 23.2 47.8 10727/C09 −13.5 16.6 21.7 37.910727/C10 −35.3 85.3 45.7 94.4 10727/C11 −25.6 −15.6 22.4 14.5 10727/D023.2 22.6 5.7 51.6 10727/D03 3.1 39.4 −3.0 24.0 10727/D04 25.9 39.6 6.476.0 10727/D05 8.5 3.4 −0.1 39.9 10727/D06 13.1 8.6 10.8 24.4 10727/D0719.7 10.5 −14.7 50.6 10727/D08 14.1 −0.5 5.0 8.5 10727/D09 8.2 15.1 7.217.9 10727/D10 11.4 86.2 9.4 79.9 10727/D11 10.5 23.7 17.4 17.310727/E02 9.3 22.4 −6.7 28.0 10727/E03 11.1 35.5 5.7 28.8 10727/E04 46.182.1 −7.4 98.4 10727/E05 17.1 12.9 −7.4 12.1 10727/E06 14.2 −9.3 9.4−2.2 10727/E07 20.1 7.1 10.1 45.2 10727/E08 14.2 25.6 23.9 27.010727/E09 9.3 15.1 15.9 28.4 10727/E10 9.7 85.1 5.0 96.6 10727/E11 37.3−33.4 7.9 −5.4 10727/F02 15.9 −0.5 11.5 52.0 10727/F03 8.9 36.8 −3.722.0 10727/F04 15.3 17.9 −10.3 92.0 10727/F05 21.8 −9.1 −3.7 6.010727/F06 14.5 4.9 8.6 37.7 10727/F07 21.4 −8.9 2.1 17.9 10727/F08 12.5−5.4 10.1 36.9 10727/F09 −45.2 −2.0 21.7 9.3 10727/F10 15.9 74.1 9.493.4 10727/F11 17.3 −2.6 18.1 −3.0 10727/G02 7.1 37.5 −20.5 81.510727/G03 −3.5 19.4 −10.3 40.5 10727/G04 27.2 80.6 −27.0 94.0 10727/G058.0 11.2 −2.3 7.1 10727/G06 2.9 −12.1 −12.5 31.1 10727/G07 7.2 5.4 −24.129.6 10727/G08 15.7 −19.6 −7.4 21.8 10727/G09 5.7 −9.7 10.8 18.810727/G10 −5.6 85.1 10.8 99.2 10727/G11 6.9 −3.5 15.9 −0.8 10728/A02−12.3 9.2 −7.9 25.6 10728/A03 −7.3 −25.8 −7.9 29.2 10728/A04 −3.5 28.015.6 28.5 10728/A05 −10.8 17.7 4.5 31.8 10728/A06 −10.4 17.2 −3.1 19.710728/A07 −21.6 59.6 31.1 28.5 10728/A08 −1.4 24.1 0.5 40.2 10728/A09−5.5 19.3 10.3 53.1 10728/A10 −16.3 −3.4 1.8 77.2 10728/A11 −2.3 −0.6−9.3 58.8 10728/B02 −11.1 −10.5 −0.4 61.2 10728/B03 −1.3 −36.6 10.3 74.410728/B04 −6.0 −2.0 9.8 67.2 10728/B05 −12.3 26.9 9.4 60.4 10728/B06 4.738.1 7.6 56.0 10728/B07 31.4 11.1 20.9 82.2 10728/B08 14.8 34.7 −6.677.0 10728/B09 1.7 31.7 −0.4 81.7 10728/B10 3.9 16.8 2.7 79.3 10728/B11−1.0 48.2 −12.4 80.3 10728/C02 −32.1 −35.4 42.3 15.5 10728/C03 10.5 9.724.9 16.9 10728/C04 −0.0 16.1 27.2 33.6 10728/C05 −21.7 16.1 23.2 33.710728/C06 8.4 4.2 2.7 22.9 10728/C07 −7.2 8.3 8.9 46.3 10728/C08 −2.217.5 9.4 25.5 10728/C09 14.5 −6.8 8.1 31.6 10728/C10 6.1 4.4 11.2 28.710728/C11 −10.1 21.8 8.5 45.2 10728/D02 −0.3 9.9 9.8 21.4 10728/D03 10.210.8 32.0 13.5 10728/D04 6.8 −1.1 26.7 23.1 10728/D05 4.9 12.7 7.2 29.510728/D06 10.4 5.8 5.8 23.2 10728/D07 8.1 2.4 2.3 21.8 10728/D08 13.56.9 2.7 34.7 10728/D09 10.5 −2.9 −3.9 27.6 10728/D10 17.9 18.6 −3.9 30.510728/D11 15.9 22.1 −10.2 52.5 10728/E02 5.4 7.4 15.2 5.4 10728/E03 13.29.5 12.0 11.9 10728/E04 5.5 10.1 23.2 25.6 10728/E05 17.4 7.4 5.8 53.410728/E06 6.6 −4.7 12.0 26.4 10728/E07 9.6 21.8 28.0 79.8 10728/E08 15.25.1 29.4 46.3 10728/E09 9.0 0.1 22.3 40.0 10728/E10 24.7 −20.8 13.8 57.210728/E11 16.3 −5.9 8.9 53.1 10728/F02 2.9 4.4 7.2 25.6 10728/F03 6.8−0.2 −9.3 18.7 10728/F04 14.2 5.1 7.2 47.9 10728/F05 6.0 −5.9 −0.4 53.310728/F06 14.4 −1.5 1.8 28.2 10728/F07 2.4 −2.2 −0.8 62.6 10728/F08 14.5−13.5 8.9 62.8 10728/F09 5.9 −13.0 1.4 23.4 10728/F10 18.0 −6.3 4.9 48.710728/F11 16.7 0.8 −12.4 72.5 10728/G02 2.3 −10.2 0.9 7.1 10728/G03 14.3−2.0 −8.4 8.8 10728/G04 21.8 −8.2 0.5 20.9 10728/G05 9.4 7.2 −4.4 63.110728/G06 13.5 −14.1 −13.3 25.3 10728/G07 22.6 −12.3 −17.3 42.410728/G08 21.4 −5.7 −11.9 42.3 10728/G09 6.8 −8.0 6.3 22.2 10728/G1010.4 −12.5 −0.8 27.9 10728/G11 3.2 16.1 −12.8 71.4 10729/A02 15.5 10.0−25.7 28.1 10729/A03 4.7 27.0 1.9 27.5 10729/A04 −4.0 58.8 −16.6 45.410729/A05 −17.7 23.4 −6.8 38.8 10729/A06 −10.9 36.5 −8.6 29.8 10729/A07−10.0 49.0 −36.7 51.1 10729/A08 −13.3 37.8 −23.4 48.1 10729/A09 0.4 25.711.0 80.3 10729/A10 0.7 28.7 −12.8 34.8 10729/A11 4.9 15.5 −11.7 49.910729/B02 13.8 34.9 −10.2 77.2 10729/B03 11.2 38.2 −9.4 57.3 10729/B040.1 63.7 −22.7 43.8 10729/B05 −5.2 50.6 −25.7 51.0 10729/B06 2.0 56.9−19.2 61.1 10729/B07 −13.4 69.0 −33.2 58.2 10729/B08 −14.7 53.2 −13.666.0 10729/B09 −16.0 51.6 −6.4 47.2 10729/B10 −0.7 68.3 −13.9 32.610729/B11 7.8 18.8 4.2 36.6 10729/C02 6.0 16.9 9.1 18.2 10729/C03 11.025.7 13.7 13.5 10729/C04 −2.5 35.9 4.2 20.7 10729/C05 5.8 21.8 −5.6 15.510729/C06 3.8 38.2 3.1 15.2 10729/C07 −22.4 60.8 −1.8 58.4 10729/C08−20.3 25.4 −13.6 55.7 10729/C09 −26.4 33.2 −34.8 60.4 10729/C10 2.5 45.73.5 15.8 10729/C11 10.4 35.9 −17.4 41.3 10729/D02 12.2 5.7 15.6 31.710729/D03 15.3 15.5 14.1 22.6 10729/D04 −5.7 18.8 −12.8 33.1 10729/D052.2 22.1 2.3 28.1 10729/D06 0.2 45.7 2.7 30.2 10729/D07 −15.3 21.4 −20.025.5 10729/D08 −26.2 10.3 −21.1 27.6 10729/D09 −9.6 22.1 −12.1 34.810729/D10 4.1 11.3 −11.3 36.1 10729/D11 −2.0 19.2 0.1 18.8 10729/E0226.6 8.0 28.4 11.7 10729/E03 6.9 20.1 29.2 27.5 10729/E04 9.7 19.5 26.59.8 10729/E05 46.8 12.6 29.9 13.4 10729/E06 12.1 43.7 24.7 −0.710729/E07 4.1 26.7 29.6 21.6 10729/E08 10.9 40.1 11.0 73.7 10729/E09 6.929.6 −11.7 85.0 10729/E10 5.7 50.3 11.8 7.5 10729/E11 70.9 25.7 22.450.8 10729/F02 18.9 −14.0 20.1 19.5 10729/F03 30.0 10.6 33.7 27.810729/F04 16.0 13.3 25.4 44.9 10729/F05 15.4 −4.8 31.5 33.8 10729/F0636.4 15.9 29.6 44.3 10729/F07 −5.8 6.7 6.1 37.3 10729/F08 −3.4 10.3 0.844.6 10729/F09 −2.6 13.3 8.8 38.2 10729/F10 20.0 58.5 15.2 39.010729/F11 −1.5 25.4 7.2 15.2 10729/G02 18.8 −4.8 16.7 31.3 10729/G0310.4 14.6 13.7 20.1 10729/G04 12.2 52.9 1.6 18.2 10729/G05 8.7 4.4 9.922.6 10729/G06 10.9 15.2 11.8 26.0 10729/G07 −2.5 −0.8 14.4 38.210729/G08 −1.0 6.0 0.8 39.9 10729/G09 −3.3 20.8 1.9 49.6 10729/G10 −9.160.1 −13.2 26.7 10729/G11 −0.5 23.4 3.8 15.4 10730/A02 −3.7 27.5 −23.139.5 10730/A03 −3.2 34.4 −11.2 62.3 10730/A04 −9.9 37.2 −5.1 70.610730/A05 −10.8 18.6 2.8 42.7 10730/A06 −7.0 6.7 6.3 61.0 10730/A07−18.9 10.4 −23.9 55.4 10730/A08 −2.9 10.4 −6.0 69.0 10730/A09 1.9 1.1−4.7 69.5 10730/A10 0.5 56.1 1.0 68.7 10730/A11 6.8 56.4 −6.41 91.010730/B02 5.0 10.4 5.4 66.3 10730/B03 −0.5 46.8 17.3 78.3 10730/B04 12.836.5 7.2 73.2 10730/B05 −0.5 8.5 −2.9 71.1 10730/B06 2.4 25.0 7.6 71.310730/B07 0.6 57.1 2.4 63.1 10730/B08 4.4 48.4 0.2 91.8 10730/B09 9.414.2 15.1 70.6 10730/B10 15.2 15.8 19.0 69.5 10730/B11 1.9 70.2 −13.981.7 10730/C02 48.8 2.7 26.5 31.2 10730/C03 25.5 −12.1 36.5 43.210730/C04 46.1 0.1 15.5 43.2 10730/C05 11.4 −9.8 8.5 46.1 10730/C06 5.38.5 7.6 34.7 10730/C07 7.3 20.3 1.0 37.4 10730/C08 −2.3 24.3 8.5 56.510730/C09 14.0 28.2 18.1 42.9 10730/C10 15.4 20.5 44.4 40.3 10730/C11−8.0 38.4 16.4 66.6 10730/D02 12.4 18.6 24.3 34.7 10730/D03 8.4 9.9 19.034.2 10730/D04 9.1 10.4 20.8 33.6 10730/D05 11.9 12.6 −1.6 38.110730/D06 5.8 35.3 −2.0 55.9 10730/D07 8.8 43.0 5.0 52.5 10730/D08 8.644.9 12.9 −13.6 10730/D09 9.8 45.1 −1.6 59.1 10730/D10 −15.3 16.7 −3.318.5 10730/D11 7.7 2.0 −0.7 9.7 10730/E02 24.8 17.7 16.4 18.8 10730/E0334.5 65.3 14.6 53.3 10730/E04 22.1 13.5 18.6 35.2 10730/E05 8.7 15.828.7 49.0 10730/E06 11.1 1.5 26.0 52.8 10730/E07 12.0 18.8 30.0 37.110730/E08 25.1 6.2 48.4 40.3 10730/E09 21.8 21.7 20.3 33.9 10730/E1026.0 9.3 39.6 63.6 10730/E11 29.1 19.1 31.7 77.2 10730/F02 18.4 2.9 20.3−6.2 10730/F03 11.7 10.4 1.5 −0.6 10730/F04 18.3 −4.8 28.7 36.010730/F05 19.6 −16.3 19.5 23.5 10730/F06 21.9 −0.6 3.2 56.5 10730/F0767.5 27.3 −2.0 60.7 10730/F08 2.1 0.8 −0.3 46.4 10730/F09 14.4 17.9 13.371.1 10730/F10 13.4 6.2 1.9 42.1 10730/F11 −1.3 −24.1 4.5 53.6 10730/G0223.3 20.8 18.1 41.1 10730/G03 15.2 −6.9 44.0 43.2 10730/G04 7.4 −6.721.6 47.7 10730/G05 22.3 −18.2 65.0 35.8 10730/G06 8.2 −2.7 0.2 17.710730/G07 8.3 6.4 19.9 26.2 10730/G08 23.3 9.5 20.3 16.6 10730/G09 18.7−20.3 23.0 16.4 10730/G10 11.3 3.1 22.1 42.1 10730/G11 −1.4 26.2 −0.346.1 10731/A02 2.7 14.8 −3.9 23.9 10731/A03 2.5 10.8 7.5 54.8 10731/A045.0 20.2 5.1 43.6 10731/A05 −6.5 34.3 14.1 85.8 10731/A06 −5.5 30.1 1.353.0 10731/A07 −4.3 39.4 4.6 49.5 10731/A08 −13.8 25.7 −2.5 59.910731/A09 −2.7 21.9 −14.4 46.7 10731/A10 −5.3 26.3 −3.5 41.2 10731/A113.1 −16.1 −0.1 53.4 10731/B02 6.5 15.5 13.2 71.6 10731/B03 1.9 12.3 9.960.9 10731/B04 12.0 31.3 0.3 71.0 10731/B05 3.8 35.9 17.9 86.0 10731/B066.2 37.5 5.6 56.2 10731/B07 11.7 29.1 6.0 41.6 10731/B08 6.2 37.2 −23.457.4 10731/B09 −0.5 15.0 0.3 29.6 10731/B10 1.3 50.5 4.6 72.9 10731/B116.9 55.2 −13.0 58.2 10731/C02 3.1 −6.9 −2.5 11.1 10731/C03 4.5 9.1 11.338.7 10731/C04 10.5 31.0 15.1 32.5 10731/C05 14.9 35.5 22.7 78.310731/C06 13.8 23.1 7.0 18.2 10731/C07 70.4 35.5 31.3 −11.6 10731/C0810.2 23.6 −3.0 25.8 10731/C09 15.1 16.8 −6.3 22.7 10731/C10 19.7 20.96.5 23.3 10731/C11 5.5 29.6 −9.2 16.2 10731/D02 −8.4 4.9 17.9 8.710731/D03 17.3 16.3 28.4 40.2 10731/D04 9.3 15.8 6.5 24.5 10731/D05 32.753.9 46.0 92.7 10731/D06 16.1 23.2 8.0 59.7 10731/D07 12.3 25.9 2.7 45.910731/D08 25.8 16.8 −8.7 44.2 10731/D09 6.1 12.6 −2.0 23.9 10731/D1013.0 15.8 9.9 21.1 10731/D11 15.2 43.6 8.4 56.6 10731/E02 11.2 7.9 13.749.1 10731/E03 −1.4 10.4 15.6 20.7 10731/E04 23.8 13.6 30.8 55.610731/E05 7.0 17.7 27.0 82.2 10731/E06 2.6 10.4 −12.0 37.7 10731/E0712.6 38.4 3.7 45.9 10731/E08 10.5 40.1 8.9 59.0 10731/E09 52.5 17.2 23.227.0 10731/E10 33.1 25.1 21.7 35.5 10731/E11 17.9 26.4 27.9 60.710731/F02 11.1 17.7 14.1 47.5 10731/F03 7.9 8.4 11.8 40.6 10731/F04 24.55.0 3.2 17.0 10731/F05 17.6 19.5 20.3 84.4 10731/F06 2.2 7.2 −23.4 20.910731/F07 13.3 37.7 1.3 34.7 10731/F08 9.2 7.1 4.1 23.5 10731/F09 2.3−0.7 15.6 20.5 10731/F10 11.0 7.9 28.4 48.1 10731/F11 19.7 42.3 20.360.1 10731/G02 16.8 4.7 −10.1 15.2 10731/G03 12.9 7.7 6.5 33.7 10731/G0414.5 7.1 0.3 23.3 10731/G05 17.5 18.5 8.0 72.4 10731/G06 10.8 2.3 −0.633.3 10731/G07 31.6 0.7 40.8 10.9 10731/G08 18.2 13.3 −13.9 19.510731/G09 13.3 8.9 −8.7 4.4 10731/G10 −9.0 5.5 5.6 10.3 10731/G11 1.567.2 16.0 64.3 10732/A02 −12.5 5.1 10.8 53.7 10732/A03 −9.9 0.8 −3.837.4 10732/A04 −14.1 −10.6 −9.4 34.8 10732/A05 −3.9 4.6 −12.9 20.510732/A06 −0.0 −1.4 12.3 5.7 10732/A07 −19.8 −0.3 0.7 26.1 10732/A08−10.0 12.1 31.0 32.7 10732/A09 −11.2 39.7 8.8 60.3 10732/A10 10.2 6.17.3 20.3 10732/A11 −0.6 1.8 40.1 65.3 10732/B02 2.9 −26.0 23.5 78.010732/B03 8.2 −15.3 17.4 58.1 10732/B04 −1.3 −22.1 16.9 79.5 10732/B052.8 17.0 21.9 71.2 10732/B06 8.1 12.8 −12.4 74.3 10732/B07 1.6 15.8 21.475.1 10732/B08 8.0 7.8 16.9 64.4 10732/B09 14.0 2.0 18.4 69.2 10732/B1012.1 0.6 0.7 51.5 10732/B11 9.0 9.3 70.9 73.7 10732/C02 11.9 −6.5 7.340.1 10732/C03 14.7 1.4 7.3 14.0 10732/C04 12.8 −14.7 3.8 30.6 10732/C0511.2 −22.8 −17.0 18.5 10732/C06 11.8 −43.2 5.3 21.6 10732/C07 15.4 −28.64.3 26.5 10732/C08 7.6 1.6 17.9 54.5 10732/C09 8.0 −3.9 15.4 37.910732/C10 15.1 1.2 5.8 43.0 10732/C11 18.2 −5.0 16.4 31.9 10732/D02 9.28.7 −24.0 50.2 10732/D03 22.5 −18.7 26.0 24.9 10732/D04 24.6 −11.4 50.740.7 10732/D05 15.7 −36.7 4.3 30.2 10732/D06 16.3 3.6 16.4 24.310732/D07 14.7 −19.1 −3.8 43.2 10732/D08 33.3 −20.6 30.5 49.4 10732/D0915.2 −9.9 15.9 40.3 10732/D10 25.5 −16.6 24.5 33.1 10732/D11 18.8 −13.418.9 48.6 10732/E02 13.1 0.8 4.8 33.3 10732/E03 16.7 −1.6 48.7 3.910732/E04 15.8 −10.6 29.5 8.2 10732/E05 18.7 −17.0 41.1 2.2 10732/E062.8 −11.0 16.9 −2.1 10732/E07 21.3 −8.5 42.2 15.2 10732/E08 13.6 −21.732.6 29.4 10732/E09 15.3 −7.2 46.7 18.1 10732/E10 16.7 −3.3 35.6 1.610732/E11 16.2 −32.2 47.7 41.4 10732/F02 7.0 23.1 −9.4 55.6 10732/F0331.9 54.1 51.8 68.6 10732/F04 16.2 −0.1 23.5 57.2 10732/F05 37.3 −30.712.8 58.9 10732/F06 11.6 −8.0 0.2 45.7 10732/F07 31.0 −12.5 38.6 65.510732/F08 12.6 −11.9 14.9 76.6 10732/F09 25.6 −13.4 25.5 79.7 10732/F1014.1 0.8 15.9 65.1 10732/F11 21.9 −21.5 77.5 75.2 10732/G02 8.1 −0.710.3 39.5 10732/G03 0.8 −20.0 36.1 38.1 10732/G04 12.6 8.0 25.0 24.910732/G05 17.2 3.8 15.4 15.2 10732/G06 26.5 −12.1 0.2 16.2 10732/G07 4.6−21.9 21.4 23.9 10732/G08 10.0 −20.4 37.6 44.7 10732/G09 16.9 −34.8 9.833.9 10732/G10 14.0 −38.2 20.4 45.7 10732/G11 10.9 −33.7 38.6 63.010733/A02 −5.2 25.9 11.5 74.6 10733/A03 45.0 33.6 23.2 24.9 10733/A04−11.2 32.8 −14.1 24.0 10733/A05 −23.3 55.2 −4.0 18.2 10733/A06 −16.645.1 −24.3 33.7 10733/A07 −27.4 28.5 −12.9 27.2 10733/A08 −17.1 19.5−10.1 27.2 10733/A09 −11.9 25.9 −7.6 22.1 10733/A10 −9.3 14.2 −13.3 21.110733/A11 15.0 23.0 4.2 43.5 10733/B02 −7.4 31.6 14.7 74.6 10733/B03 3.114.4 35.8 62.2 10733/B04 −3.3 28.5 24.9 56.3 10733/B05 −1.1 26.7 27.361.3 10733/B06 4.6 43.6 −9.2 71.4 10733/B07 1.2 32.7 4.2 73.5 10733/B08−16.0 32.5 −15.7 65.5 10733/B09 −2.6 21.1 7.0 64.5 10733/B10 5.7 11.8−59.6 65.1 10733/B11 22.5 12.5 23.7 36.6 10733/C02 5.8 31.6 15.1 71.810733/C03 17.0 14.4 28.1 29.3 10733/C04 8.4 29.0 19.2 18.4 10733/C0511.5 17.2 11.1 23.2 10733/C06 4.7 22.7 20.0 4.1 10733/C07 1.2 16.7 4.610.2 10733/C08 −28.5 65.8 −3.6 85.7 10733/C09 −18.0 46.0 91.9 16.310733/C10 −7.6 36.0 −6.4 20.5 10733/C11 42.8 15.8 62.2 35.1 10733/D023.1 12.5 17.6 63.4 10733/D03 33.2 11.2 40.7 32.8 10733/D04 15.5 19.926.5 37.7 10733/D05 16.5 10.6 16.8 25.1 10733/D06 17.9 30.8 1.3 −19.410733/D07 −1.4 37.4 0.9 −6.8 10733/D08 −8.3 38.3 42.3 80.0 10733/D09 9.848.3 33.8 38.7 10733/D10 2.9 46.8 −10.1 22.8 10733/D11 1.0 33.7 −4.031.6 10733/E02 0.8 −1.3 20.8 60.5 10733/E03 42.6 10.7 43.1 26.810733/E04 2.1 45.4 −13.7 17.5 10733/E05 10.6 58.3 −33.2 2.9 10733/E0613.5 37.3 22.4 10.4 10733/E07 13.2 19.9 29.3 −10.1 10733/E08 −5.1 54.275.2 81.1 10733/E09 13.4 72.4 35.8 62.6 10733/E10 5.5 31.3 10.3 52.810733/E11 5.5 31.6 15.9 71.8 10733/F02 −15.7 11.3 3.8 71.6 10733/F0317.5 −3.6 24.5 24.2 10733/F04 21.4 76.3 −28.7 65.1 10733/F05 26.2 84.6−25.1 65.1 10733/F06 19.3 17.8 −4.8 20.9 10733/F07 16.4 19.2 1.7 −16.410733/F08 −13.2 17.2 −32.4 66.6 10733/F09 −2.1 30.1 −0.3 52.8 10733/F108.5 21.9 −5.6 24.4 10733/F11 4.1 0.6 −17.8 44.4 10733/G02 8.3 −6.2 −7.664.5 10733/G03 24.7 0.7 12.7 30.5 10733/G04 11.5 10.6 11.9 20.310733/G05 19.2 1.5 −1.1 1.8 10733/G06 37.0 5.2 0.1 0.8 10733/G07 19.518.1 −6.8 8.5 10733/G08 2.5 44.2 68.7 79.0 10733/G09 77.8 38.7 −17.041.4 10733/G10 12.7 18.2 −58.0 41.9 10733/G11 3.3 −1.0 −4.4 32.610734/A02 4.1 0.0 −3.8 51.1 10734/A03 10.1 18.5 22.3 87.8 10734/A04 0.611.4 11.7 68.0 10734/A05 9.1 22.6 2.9 69.9 10734/A06 −6.4 −6.4 −9.9 46.910734/A07 −9.4 15.2 21.9 89.3 10734/A08 0.1 6.8 9.1 71.5 10734/A09 −7.927.3 −9.5 88.4 10734/A10 4.4 27.8 26.3 55.4 10734/A11 6.3 12.5 5.5 51.910734/B02 8.5 −8.9 −2.9 61.9 10734/B03 21.7 45.1 13.0 90.1 10734/B04 2.838.7 14.4 88.4 10734/B05 −2.3 17.8 56.3 67.8 10734/B06 −0.9 54.0 0.291.2 10734/B07 9.1 65.5 18.8 93.2 10734/B08 −0.5 19.3 −2.4 56.110734/B09 −32.3 34.9 12.6 94.3 10734/B10 15.7 60.7 7.7 82.6 10734/B1112.6 50.9 −5.5 83.6 10734/C02 −3.9 −6.7 36.0 78.6 10734/C03 −5.6 48.624.5 88.2 10734/C04 −37.6 38.1 24.5 90.7 10734/C05 −10.3 9.3 3.8 52.710734/C06 −1.7 18.4 −0.2 48.3 10734/C07 −2.7 41.0 32.0 96.8 10734/C08−34.2 35.1 5.5 93.2 10734/C09 −13.3 36.2 11.3 88.6 10734/C10 10.1 24.417.4 11.6 10734/C11 6.3 18.0 9.1 23.9 10734/D02 −11.5 5.2 6.4 46.010734/D03 17.4 19.6 24.1 78.6 10734/D04 6.1 −10.7 13.5 46.9 10734/D052.4 −9.6 8.2 55.0 10734/D06 0.0 1.3 −9.1 30.6 10734/D07 14.7 51.1 28.192.0 10734/D08 2.5 −13.7 2.0 49.8 10734/D09 −11.6 21.0 42.2 88.010734/D10 11.1 −4.4 9.9 20.6 10734/D11 9.8 14.6 17.0 33.9 10734/E02 7.9−10.8 50.1 66.9 10734/E03 26.9 55.0 27.2 99.3 10734/E04 10.7 −7.8 26.788.9 10734/E05 10.6 7.9 17.9 63.6 10734/E06 28.4 6.3 13.5 50.6 10734/E0727.9 82.4 8.2 100.8 10734/E08 26.6 24.2 13.0 89.1 10734/E09 8.0 73.0 1.196.2 10734/E10 18.5 −5.0 29.8 27.9 10734/E11 19.2 −8.0 16.1 67.110734/F02 6.2 0.7 10.4 55.0 10734/F03 4.2 24.8 −24.1 86.8 10734/F04 −2.63.9 25.0 76.5 10734/F05 9.8 −15.6 −1.1 73.8 10734/F06 11.0 −17.1 −21.464.2 10734/F07 6.6 33.7 −5.1 95.7 10734/F08 4.8 −23.6 −6.0 66.310734/F09 −3.7 3.1 −17.4 93.9 10734/F10 14.8 −8.3 25.8 44.8 10734/F1113.3 −15.6 16.1 47.3 10734/G02 1.5 3.4 14.8 63.6 10734/G03 18.7 82.8−3.8 93.4 10734/G04 −1.1 62.9 16.1 72.1 10734/G05 7.4 −0.3 2.9 57.710734/G06 16.5 12.5 −18.8 43.1 10734/G07 21.9 51.1 −25.0 96.6 10734/G0811.6 33.7 0.2 82.2 10734/G09 8.5 21.4 −7.7 84.7 10734/G10 10.8 3.8 9.919.3 10734/G11 8.7 4.1 −25.4 20.2

1. A combinatorial library of indolinone compounds, comprising at leastten indolinones that can be formed by reacting oxindoles with aldehydes.2. The combinatorial library of claim 1 wherein said oxindoles are typeA oxindoles.
 3. The combinatorial library of claim 1 wherein saidaldehydes are type B aldehydes.
 4. A method of making an indolinonecomprising the steps of (a) creating a combinatorial library ofindolinones by reacting a series of oxindoles with a series ofaldehydes, (b) testing said indolinones in biological assays, (c)selecting one or more indolinones with favorable activity; and (d)synthesizing one or more of said indolinones selected in step (c).
 5. A3-[(indole-3-yl)methylene]-2-indolinone compound having a substituent atthe 1′ position of the indole, where the substituent at the 1′ positionis selected from the group consisting of, (a) alkyl that is optionallysubstituted with a monocyclic or bicyclic five, six, eight, nine, or tenmembered heterocyclic ring, where the ring is optionally substitutedwith one or more halogen, aldehyde, or trihalomethyl substituents; (b)five, six, eight, nine, or ten membered monocyclic or bicyclicheterocyclic ring, where the ring is optionally substituted with one ormore halogen or trihalomethyl substituents; (c) an aldehyde or ketone offormula —CO—R₁₂, where R₁₂ is selected from the group consisting ofhydrogen, alkyl, and a five or six membered heterocyclic ring; (d) acarboxylic acid of formula —(R₁₃)n-COOH or ester of formula—(R₁₄)m-COO—R₁₅, where R₁₃, R₁₄, and R₁₅ are independently selected fromthe group consisting of alkyl and a five or six membered heterocyclicring and m and n are independently 0 or 1; (e) a sulfone of formula—(SO2)-R₁₆, where R₁₆ is selected from the group consisting of alkyl anda five or six membered heterocyclic ring, where the ring is optionallysubstituted with an alkyl moiety; (f) -(R¹⁷)_(n)-(indole-1-yl) or—(R₁₈)m-CHOH—(R₁₉)p-(indole-1-yl), where the indol moiety is optionallysubstituted with an aldehyde and R₁₇, R₁₈, and R₁₉ are alkyl and m, n,and p are independently 0 or 1; and (g) taken together with a 2′substituent of the indole ring forms a tricyclic moiety, where each ringin the tricyclic moiety is a five or six membered heterocyclic ring. 6.The compound, salt, isomer, metabolite, ester, amide, or prodrug ofclaim 5, wherein said compound has the formula,

where (a) R₁ is selected from the group consisting of, (i) alkyl that isoptionally substituted with a monocyclic or bicyclic five, six, eight,nine, or ten membered heterocyclic ring, where the ring is optionallysubstituted with one or more halogen, aldehyde, or trihalomethylsubstituents; (ii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents; (iii) analdehyde or ketone of formula —CO—R₁₂, where R₁₁ is selected from thegroup consisting of hydrogen, alkyl, or a five or six memberedheterocyclic ring; (iv) a carboxylic acid of formula —(R₁₃)_(n)—COOH orester of formula —(R₁₄)m-COO—R₁₅, where R₁₃, R₁₄, and R₁₅ and areindependently selected from the group consisting of alkyl or a five orsix membered heterocyclic ring and n and m are independently 0 or 1; (v)a sulfone of formula —(SO₂)—R₁₆, where R₁₆ is selected from the groupconsisting of alkyl or a five or six membered heterocyclic ring, wherethe ring is optionally substituted with an alkyl moiety; (vi)-(R₁₇)_(n)-(indole-1-yl) or —(R₁₈)m-CHOH—(R₁₉)p-(indole-1-yl), where theindol moiety is optionally substituted with an aldehyde and R₁₇, R₁₈,and R₁₉ are alkyl and n, m, and p are independently 0 or 1; (vii) takentogether with a 2′ substituent of the indole ring forms a tricyclicmoiety, where each ring in the tricyclic moiety is a five or sixmembered heterocyclic ring; (b) R₂, R₃, R₄, R₅, and R₆ are selected fromthe group consisting of, (i) hydrogen or alkyl that is optionallysubstituted with a monocyclic or bicyclic five, six, eight, nine, or tenmembered heterocyclic ring, where the ring is optionally substitutedwith one or more halogen, aldehyde, or trihalomethyl substituents; (ii)five, six, eight, nine, or ten membered monocyclic or bicyclicheterocyclic ring, where the ring is optionally substituted with one ormore halogen or trihalomethyl substituents; (iii) an aldehyde or ketoneof formula —CO—R₂₀, where R₂₀ is selected from the group consisting ofhydrogen, alkyl, or a five or six membered heterocyclic ring; (iv) acarboxylic acid of formula —(R₂₁)n-COOH or ester of formula—(R₂₂)—COO—R₂₃, where R₂₁, R₂₂, and R₂₃ and are independently selectedfrom the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1; (v) halogen oran alcohol of formula (R24)m-OH or an ether of formula —(R₂₄)_(n)—O—R₂₅,where R₂₄ and R25 are independently selected from the group consistingof alkyl and a five or six membered heterocyclic ring and m and n areindependently 0 or 1; (vi) —NR₂₆R₂₇, where R₂₆ and R₂₇ are independentlyselected from the group consisting of hydrogen, oxygen, alkyl, and afive or six membered heterocyclic ring; or —NHCOR₂₈, where R₂₈ isselected from the group consisting of hydroxyl, alkyl, and a five or sixmembered heterocyclic ring, where the ring is optionally substitutedwith alkyl, halogen, carboxylate, or ester; (vii) —SO2NR₂₉R₃₀, where R₂₉and R₃₀ are selected from the group consisting of hydrogen, oxygen,alkyl, and a five or six membered heterocyclic ring; (viii) any two ofR₃, R₄, R₅, or R₆ taken together form a bicyclic or tricyclichetercyclic moiety fused to the six membered ring of the indole, whereeach ring in the multicyclic moiety is a five or six memberedheterocyclic ring; (c) R₇, R₈, R₉, and R₁₀ are independently selectedfrom the group consisting of, (i) hydrogen or alkyl that is optionallysubstituted with a monocyclic or bicyclic five, six, eight, nine, or tenmembered heterocyclic ring, where the ring is optionally substitutedwith one or more halogen, aldehyde, or trihalomethyl substituents; (ii)five, six, eight, nine, or ten membered monocyclic or bicyclicheterocyclic ring, where the ring is optionally substituted with one ormore halogen or trihalomethyl substituents; (iii) an aldehyde or ketoneof formula —CO—R₃₁, where R₃₁ is selected from the group consisting ofhydrogen, alkyl, or a five or six membered heterocyclic ring; (iv) acarboxylic acid of formula —(R₃₂)n-COOH or ester of formula—(R₃₃)m-COO—R₃₄, where R₃₂, R₃₃, and R34 and are independently selectedfrom the group consisting of alkyl or a five or six memberedheterocyclic ring and n and m are independently 0 or 1; (v) halogen oran alcohol of formula (R₃₅)m-OH or an ether of formula —(R₃₅)n-O—R₃₆,where R₃₅ and R₃₆ are independently chosen from the group consisting ofalkyl or a five or six membered heterocyclic ring and m and n areindependently 0 or 1; (vi) —NR₃₇R₃₈, where R₃₇ and R₃₈ are independentlyselected from the group consisting of hydrogen, oxygen, alkyl, and afive or six membered heterocyclic ring; or NHCOR₃₉, where R₃₉ isselected from the group consisting of hydroxyl, alkyl, and a five or sixmembered heterocyclic ring, where the ring is optionally substitutedwith alkyl, halogen, carboxylate, or ester; (vii) —SO2NR₄₀R₄₁, where R₄₀and R₄₁ are selected from the group consisting of hydrogen, oxygen,alkyl, and a five or six membered heterocyclic ring; (viii) any two ofR₇, R₈, R₉, or R₁₀ taken together form a bicyclic or tricyclichetercyclic moiety fused to the six membered ring of the indole, whereeach ring in the multicyclic moiety is a five or six memberedheterocyclic ring; and (d) R₁₁ is hydrogen or alkyl; provided that atleast one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, or R₁₀ is alkyl orprovided that at least four of R₁, R₂, R₃, R₄, R₅, or R₆ are nothydrogen.
 7. An optionally substituted3-[(tetrahydroindole-2-yl)methylene]-2-indolinone or3-[(cyclopentano-b-pyrrol-2-yl)methylene]-2-indolinone compound.
 8. Theindolinone compound of claim 7 of formula XIX or XX,

or a pharmaceutically acceptable salt, isomer, metabolite, ester, amide,or prodrug thereof where (a) R₁ is selected from the group consistingof, (i) alkyl that is optionally substituted with a monocyclic orbicyclic five, six, eight, nine, or ten membered heterocyclic ring,where the ring is optionally substituted with one or more halogen, ortrihalomethyl substituents; (ii) five, six, eight, nine, or ten memberedmonocyclic or bicyclic heterocyclic ring, where the ring is optionallysubstituted with one or more halogen or trihalomethyl substituents;(iii) ketone of formula —CO—R₁₂, where R₁₁ is selected from the groupconsisting of hydrogen, alkyl, or a five or six membered heterocyclicring; (iv) a carboxylic acid of formula —(R₁₃)_(n)—COOH or ester offormula —(R₁₄)_(m)—COO—R₁₅, where R₁₃, R₁₄, and R₁₅ and areindependently selected from the group consisting of alkyl or a five orsix membered heterocyclic ring and n and m are independently 0 or 1; (v)a sulfone of formula —(SO₂)—R₁₆, where R₁₆ is selected from the groupconsisting of alkyl or a five or six membered heterocyclic ring, wherethe ring is optionally substituted with an alkyl moiety; (vi)-(R₁₇)_(n)-(indole-1-yl) or —(R₁₈)_(m)—CHOH—(R₁₉)p-(indole-1-yl), wherethe indolemoiety is optionally substituted with an aldehyde and R₁₇,R₁₈, and R₁₉ are alkyl and n, m, and p are independently 0 or 1; (vii)taken together with a 2′ substituent of the indole ring forms atricyclic moiety, where each ring in the tricyclic moiety is a five orsix membered heterocyclic ring; (b) R₂, R₃, R₃′, R₄, R₄′, R₅, R₅′, R₆,and R₆′ are selected from the group consisting of, (i) hydrogen; (ii)alkyl that is optionally substituted with a monocyclic or bicyclic five,six, eight, nine, or ten membered heterocyclic ring, where the ring isoptionally substituted with one or more halogen, or trihalomethylsubstituents; (iii) five, six, eight, nine, or ten membered monocyclicor bicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents; (iv) ketone offormula —CO—R₂₀, where R₂₀ is selected from the group consisting ofhydrogen, alkyl, or a five or six membered heterocyclic ring; (v) acarboxylic acid of formula —(R₂₁)_(n)—COOH or ester of formula—(R₂₂)—COO—R₂₃, where R₂₁, R₂₂, and R₂₃ and are independently selectedfrom the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1; (vi) halogen;(vii) an alcohol of formula (R₂₄)_(m)—OH or an ether of formula—(R₂₄)_(n)—O—R₂₅, where R₂₄ and R₂₅ are independently selected from thegroup consisting of alkyl and a five or six membered heterocyclic ringand m and n are independently 0 or 1; (viii) —NR₂₆R₂₇, where R₂₆ and R₂₇are independently selected from the group consisting of hydrogen,oxygen, alkyl, and a five or six membered heterocyclic ring; (ix)—NHCOR₂₈, where R₂₈ is selected from the group consisting of hydroxyl,alkyl, and a five or six membered heterocyclic ring, where the ring isoptionally substituted with alkyl, halogen, carboxylate, or ester; (x)—SO2NR₂₉R₃₀, where R₂₉ and R₃₀ are selected from the group consisting ofhydrogen, oxygen, alkyl, and a five or six membered heterocyclic ring;(xi) any two of R₃, R_(3′), R₄, R_(4′), R₅ , R_(5′), R₆, or R_(6′) takentogether form a bicyclic or tricyclic hetercyclic moiety fused to thesix membered ring of the indole, where each ring in the multicyclicmoiety is a five or six membered heterocyclic ring; (c) R₇, R₈, R₉, andR₁₀ are independently selected from the group consisting of, (i)hydrogen; (ii) alkyl that is optionally substituted with a monocyclic orbicyclic five, six, eight, nine, or ten membered heterocyclic ring,where the ring is optionally substituted with one or more halogen, ortrihalomethyl substituents; (iii) five, six, eight, nine, or tenmembered monocyclic or bicyclic heterocyclic ring, where the ring isoptionally substituted with one or more halogen or trihalomethylsubstituents; (iv) ketone of formula —CO—R₃₁, where R₃₁ is selected fromthe group consisting of hydrogen, alkyl, or a five or six memberedheterocyclic ring; (v) a carboxylic acid of formula —(R₃₂)_(n)—COOH orester of formula —(R₃₃)_(m)—COO—R₃₄, where R₃₂, R₃₃, and R₃₄ and areindependently selected from the group consisting of alkyl or a five orsix membered heterocyclic ring and n and m are independently 0 or 1;(vi) halogen; (vii) an alcohol of formula (R₃₅)_(m)—OH or an ether offormula —(R₃₅)_(n)—O—R₃₆, where R₃₅ and R₃₆ are independently chosenfrom the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1; (viii) —NR₃₇R₃₈,where R₃₇ and R₃₈ are independently selected from the group consistingof hydrogen, oxygen, alkyl, and a five or six membered heterocyclicring; (ix) —NHCOR₃₉, where R₃₉ is selected from the group consisting ofhydroxyl, alkyl, and a five or six membered heterocyclic ring, where thering is optionally substituted with alkyl, halogen, carboxylate, orester; (x) —SO2NR₄₀R₄₁, where R₄₀ and R₄₁ are selected from the groupconsisting of hydrogen, oxygen, alkyl, and a five or six memberedheterocyclic ring; (xi) any two of R₇, R₈, R₉, or R₁₀ taken togetherform a bicyclic or tricyclic hetercyclic moiety fused to the sixmembered ring of the indole, where each ring in the multicyclic moietyis a five or six membered heterocyclic ring; and (d) R₁₁ is hydrogen oralkyl
 9. An indolinone compound having a substituent at the 5 positionof the oxindole ring, where the substituent at the 5 position of theoxindole ring is selected from the group consisting of (a) alkyl that isoptionally substituted with a monocyclic or bicyclic five, six, eight,nine, or ten membered heterocyclic ring, where the ring is optionallysubstituted with one or more halogen, or trihalomethyl substituents; (b)five, six, eight, nine, or ten membered monocyclic or bicyclicheterocyclic ring, where the ring is optionally substituted with one ormore halogen or trihalomethyl substituents; (c) a ketone of formula—CO—R₁₀, where R₁₀ is selected from the group consisting of hydrogen,alkyl, or a five or six membered heterocyclic ring; (d) a carboxylicacid of formula —(R₁₁)n-COOH or ester of formula —(R₁₂)—COO—R₁₃, whereR₁₁, R₁₂, and R₁₃ and are independently selected from the groupconsisting of alkyl or a five or six membered heterocyclic ring and mand n are independently 0 or 1; (e) halogen; (f) an alcohol of formula(R₁₄)m-OH or an ether of formula —(R₁₄)n-O—R₁₅, where R₁₄ and R₁₅ areindependently selected from the group consisting of alkyl and a five orsix membered heterocyclic ring and m and n are independently 0 or 1; (g)—NR₁₆R₁₇, where R₁₆ and R₁₇ are independently selected from the groupconsisting of hydrogen, alkyl, and a five or six membered heterocyclicring; (h) —NHCOR₁₈, where R₁₈ is selected from the group consisting ofalkyl, and a five or six membered heterocyclic ring, where the ring isoptionally substituted with alkyl, halogen, carboxylate, or ester; (i)—SO2NR₁₉R₂₀, where R₁₉ and R₂₀ are selected from the group consisting ofhydrogen, alkyl, and a five or six membered heterocyclic ring; (j) anytwo of R₄, R₅, R₆, or R₇ taken together form a bicyclic or tricyclichetercyclic moiety fused to the six membered ring of the oxindole, whereeach ring in the multicyclic moiety is a five or six memberedheterocyclic ring.
 10. The compound of claim 9 of the following formula,

where (a) R₅ is selected from the group consisting of, (i) alkyl that isoptionally substituted with a monocyclic or bicyclic five, six, eight,nine, or ten membered heterocyclic ring, where the ring is optionallysubstituted with one or more halogen, or trihalomethyl substituents;(ii) five, six, eight, nine, or ten membered monocyclic or bicyclicheterocyclic ring, where the ring is optionally substituted with one ormore halogen or trihalomethyl substituents; (iii) a ketone of formula—CO—R₁₀, where R₁₀ is selected from the group consisting of hydrogen,alkyl, or a five or six membered heterocyclic ring; (iv) a carboxylicacid of formula —(R₁₁)n-COOH or ester of formula —(R₁₂)—COO—R₁₃, whereR₁₁, R₁₂, and R₁₃ and are independently selected from the groupconsisting of alkyl or a five or six membered heterocyclic ring and mand n are independently 0 or 1; (v) halogen; (vi) an alcohol of formula(R₁₄)m-OH or an ether of formula —(R₁₄)n-O—R₁₅, where R₁₄ and R₁₅ areindependently selected from the group consisting of alkyl and a five orsix membered heterocyclic ring and m and n are independently 0 or 1;(vii) —NR₁₆R₁₇, where R₁₆ and R₁₇ are independently selected from thegroup consisting of hydrogen, alkyl, and a five or six memberedheterocyclic ring; (viii) —NHCOR₁₈, where R₁₈ is selected from the groupconsisting of alkyl, and a five or six membered heterocyclic ring, wherethe ring is optionally substituted with alkyl, halogen, carboxylate, orester; (ix) —SO₂NR₁₉R₂₀, where R₁₉ and R₂₀ are selected from the groupconsisting of hydrogen, alkyl, and a five or six membered heterocyclicring; (x) any two of R₄, R₅, R₆, or R₇ taken together form a bicyclic ortricyclic hetercyclic moiety fused to the six membered ring of theoxindole, where each ring in the multicyclic moiety is a five or sixmembered heterocyclic ring; (b) R₁ is selected from the group consistingof a five, six, eight, nine, and ten membered monocyclic or bicyclicheterocyclic ring, where the ring is optionally substituted with one ormore substituents selected from the group consisting of (i) hydrogen andalkyl that is optionally substituted with a monocyclic or bicyclic five,six, eight, nine, or ten membered heterocyclic ring, where the ring isoptionally substituted with one or more halogen, or trihalomethylsubstituents; (ii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents; (iii) a ketoneof formula —CO—R₂₁, where R₂₁ is selected from the group consisting ofhydrogen, alkyl, or a five or six membered heterocyclic ring; (iv) acarboxylic acid of formula —(R₂₂)n-COOH or ester of formula—(R₂₃)—COO—R₂₄, where R₂₂, R₂₃, and R₂₄ and are independently selectedfrom the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1; (v) halogen;(vi) an alcohol of formula (R₂₅)m-OH or an ether of formula—(R₂₅)n-O—R₂₆, where R₂₅ and R₂₆ are independently selected from thegroup consisting of alkyl and a five or six membered heterocyclic ringand m and n are independently 0 or 1; (vii) —NR₂₇R₂₈, where R₂₇ and R₂₈are independently selected from the group consisting of hydrogen, alkyl,and a five or six membered heterocyclic ring; (viii) —NHCOR₂₉, where R₂₉is selected from the group consisting of alkyl, and a five or sixmembered heterocyclic ring, where the ring is optionally substitutedwith alkyl, halogen, carboxylate, or ester; (ix) —SO₂NR₃₀R₃₁, where R₃₀and R₃₁ are selected from the group consisting of hydrogen, alkyl, and afive or six membered heterocyclic ring; (c) R₄, R₆, and R₇ areindependently selected from the group consisting of, (i) hydrogen andalkyl that is optionally substituted with a monocyclic or bicyclic five,six, eight, nine, or ten membered heterocyclic ring, where the ring isoptionally substituted with one or more halogen, or trihalomethylsubstituents; (ii) five, six, eight, nine, or ten membered monocyclic orbicyclic heterocyclic ring, where the ring is optionally substitutedwith one or more halogen or trihalomethyl substituents; (iii) a ketoneof formula —CO—R₃₂, where R₃₂ is selected from the group consisting ofhydrogen, alkyl, or a five or six membered heterocyclic ring; (iv) acarboxylic acid of formula —(R₃₃)n-COOH or ester of formula−(R₃₄)—COO—R₃₅, where R₃₃, R₃₄, and R₃₅ and are independently selectedfrom the group consisting of alkyl or a five or six memberedheterocyclic ring and m and n are independently 0 or 1; (v) halogen;(vi) an alcohol of formula (R₃₆)m-OH or an ether of formula—(R₃₆)n-O—R₃₇, where R₃₆ and R₃₇ are independently selected from thegroup consisting of alkyl and a five or six membered heterocyclic ringand m and n are independently 0 or 1; (vii) —NR₃₈R₃₉, where R₃₈ and R₃₉are independently selected from the group consisting of hydrogen, alkyl,and a five or six membered heterocyclic ring; (viii) —NHCOR₄₀, where R₄₀is selected from the group consisting of alkyl, and a five or sixmembered heterocyclic ring, where the ring is optionally substitutedwith alkyl, halogen, carboxylate, or ester; (ix) —SO₂NR₄₁R₄₂, where R₄₁and R₄₂ are selected from the group consisting of hydrogen, alkyl, and afive or six membered heterocyclic ring; and (d) R₂ is hydrogen or alkyl.11. A compound having formula XXI, wherein:

(a) A is a five or six membered ring comprised of atoms selected fromthe group consisting of oxygen, carbon, sulfer and nitrogen; (b) m iszero, 1, or 2; (c) R₁ is hydrogen, C₁—C₆ alkyl or C₂—C₆ alkanoyl; (d)one of R₂ and R₃ independently is hydrogen and the other is asubstituent selected from: (1) a C₁—C₆ alkyl group substituted by 1, 2or 3 hydroxy groups; (2) SO₃R₄ in which R₄ is hydrogen or C₁—C₆ alkylunsubstituted or substituted by 1, 2 or 3 hydroxy groups; (3) SO₂NHR₅ inwhich R₅ is as R₄ defined above or a —(CH₂)_(n)—N(C₁—C₆ alkyl)₂ group inwhich n is 2 or 3; (4) COOR₆ in which R₆ is C₁—C₆ alkyl unsubstituted orsubstituted by phenyl or by 1, 2 or 3 hydroxy groups or phenyl; (5)CONHR₇ in which R₇ is hydrogen, phenyl or C₁—C₆ alkyl substituted by 1,2 or 3 hydroxy groups or by phenyl; (6) NHSO₂R₈ in which R₈ is C₁—C₆alkyl or phenyl unsubstituted or substituted by halogen or by C₁—C₄alkyl; (7) N(R₉)₂, NHR₉ or OR₉ wherein R₉ is C₂—C₆ alkyl substituted by1, 2 or 3 hydroxy groups; (8) NHCOR₁₀, OOCR₁₀ or CH₂OOCR₁₀ in which R₁₀is C₁—C₆ alkyl substituted by 1, 2 or 3 hydroxy groups; (9) NHCONH₂;NH—C(NH₂)═NH; C(NH₂)═NH; CH₂NHC(NH₂)═NH; CH₂NH₂; OPO(OH)₂; CH₂OPO(OH)₂;PO(OH)₂; or a

wherein X is selected from the group consisting of CH₂, SO₂, CO, orNHCO(CH₂)_(p) in which p is 1, 2, or 3 and Z is CH₂, O or N—R₁₁ in whichR₁₁ is hydrogen or is as R₉ defined above.
 12. A method of making anindolinone compound of any one of claims 5-11 comprising the steps ofreaching an appropriate aldehyde and oxindol and separating theindolinone from the aldehyde and oxindol reactants.
 13. A pharmaceuticalcomposition comprising (i) a pharmaceutically acceptable carrier orexcipient and (ii) a compound according to any one of claims 5-11.
 14. Amethod for treating a disease related to unregulated tyrosine kinasesignal transduction, the method comprising the step of administering toa subject in need thereof a therapeutically effective amount of acompound according to any one of claims 5-11.
 15. A method forregulating tyrosine kinase signal transduction comprising administeringto a subject a therapeutically effective amount of a compound accordingto any one of claims 5-11.
 16. A method of preventing or treating anabnormal condition in an organism, where the abnormal condition isassociated with an aberration in a signal transduction pathwaycharacterized by an interaction between a protein kinase and a naturalbinding partner, where the method comprises the following steps: (a)administering a compound of any one of claims 5-11 to an organism; and(b) promoting or disrupting the abnormal interaction.
 17. A method ofpreventing or treating an abnormal condition in an organism, where theabnormal condition is associated with an aberration in a signaltransduction pathway characterized by an interaction between a proteinkinase and a natural binding partner, where the method comprises thefollowing steps: (a) administering a compound of any one of claims 5-11to an organism; and (b) promoting or disrupting the abnormalinteraction.